Multiple doses of sclerostin antibody romosozumab in healthy men and postmenopausal women with low bone mass: A randomized, double-blind, placebo-controlled study

Abstract

Romosozumab (formerly AMG 785/CDP7851) is a monoclonal antibody that blocks sclerostin from inhibiting osteoblast maturation and function. This double-blind, placebo-controlled, randomized, ascending multiple-dose study enrolled 32 postmenopausal women and 16 healthy men with low bone mass. Women received six doses of 1 or 2 mg/kg once every 2 weeks (Q2W) or three doses of 2 or 3 mg/kg once every 4 weeks (Q4W) or placebo; and men received 1 mg/kg Q2W or 3 mg/kg Q4W or placebo. Mean serum romosozumab exposures increased approximately dose-proportionally. Romosozumab increased serum type 1 aminoterminal propeptide (PINP) by 66-147%, decreased serum C-telopeptide (sCTX) by 15-50%, and increased lumbar spine bone mineral density by 4-7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. These data support continued investigation of sclerostin inhibition in disorders that could benefit from increased bone formation.

Bone markers and osteoporosis therapy

“…Maximum reductions in CTX were -21% for placebo, and -35% and -37% for postmenopausal women in the romosozumab Q4W regimen at 2 or 3 mg/kg respectively. In men, CTX reached a nadir of -42% on the 1 mg/kg Q2W and -50% on the 3 mg/kg Q4W romosozumab cohorts (52). Changes in BTMs reflected the salutary effects seen at BMD, with lumbar spine BMD increasing between 4-7%, and total hip between 2-3% in patients taking romosozumab.…”

“…PTH levels increased transiently in the romosozumab cohorts possibly reflecting the changes in the ionized calcium concentration. In another phase I study, ascending multiple-doses of romosozumab were administered for 12 weeks to healthy men and postmenopausal women with low bone mass (52). Patients were randomized to receive either placebo or one of the SC regimens of romosozumab [1 or 2 mg/kg once every 2 weeks (Q2W) or 2 or 3 mg/kg once every 4 weeks (Q4W)].…”

Romosozumab: from basic to clinical aspects

“…Importantly, the development of neutralizing antibodies had no discernible effects on pharmacokinetics, pharmacodynamics or safety [14].…”

“…At this point in time, we do not have all the abovementioned parameters to fully judge romosozumab. However, from the published studies, we know that administration is once monthly or every three months [12,14], a schedule that can be considered very promising. Furthermore, side effects have been reported to be similar between patients treated with the antibody or placebo, even though the small number of subjects treated for a short interval of time preclude definitive conclusions; understanding the safety of romosozumab must await the results of the larger Phase III clinical trials.…”

Are Biologic Treatments a Potential Approach to Wear- and Corrosion-related Problems?

“…The emergence of the importance of the osteocyte and the sclerostin-Wnt pathway as the central regulator of bone homeostasis in adults provides the potential that a single agent could be developed as a combination therapy for these patients. This therapy, antisclerostin (romosozumab), is currently in Phase 3 registration clinical trials for an indication as an osteoporosis therapy [31].…”