The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis.

Introduction: RANKL is an essential osteoclastic differentiation and activation factor.

Materials and Methods: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double‐blind, placebo‐controlled, single‐dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N‐telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone‐specific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers.

Results and Conclusions: Forty‐nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose‐dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of −81% in the 3.0 mg/kg AMG 162 group compared with −10% in the placebo group; serum NTX changes were −56% and 2%, respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to ∼3‐fold after 4 days in the 3.0 mg/kg dose group, but returned toward baseline with follow‐up. Albumin‐adjusted serum calcium did not decrease >10% on average in any group, and no subject had values beiow 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose‐dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis.