A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.
OBJECTIVE
Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases.


METHODS
This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed.


RESULTS
Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages.


CONCLUSIONS
A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.
Body
Jean-Jacques
JJ
Department of Medicine, Institut Jules Bordet, Brussels, Belgium. jj.body@bordet.be
Facon
Thierry
T
Coleman
Robert E
RE
Lipton
Allan
A
Geurs
Filip
F
Fan
Michelle
M
Holloway
Donna
D
Peterson
Mark C
MC
Bekker
Pirow J
PJ
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D003094:Collagen / Q000097:blood / Q000652:urine; D024042:Collagen Type I; D003404:Creatinine / Q000652:urine; D000069448:Denosumab; D004164:Diphosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D000077268:Pamidronate; D010455:Peptides / Q000097:blood / Q000652:urine; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D013997:Time Factors; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D024042:Collagen Type I; D004164:Diphosphonates; D008562:Membrane Glycoproteins; D010455:Peptides; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C052929:collagen type I trimeric cross-linked peptide; D000069448:Denosumab; D003094:Collagen; D003404:Creatinine; D000077268:Pamidronate