Denosumab in postmenopausal women with low bone mineral density.
BACKGROUND
Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action.


METHODS
The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase.


RESULTS
Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent.


CONCLUSIONS
In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis. (ClinicalTrials.gov number, NCT00043186.).
McClung
Michael R
MR
Providence Portland Medical Center, Portland, Oreg, USA. mmcclung@orost.com .
Lewiecki
E Michael
EM
Cohen
Stanley B
SB
Bolognese
Michael A
MA
Woodson
Grattan C
GC
Moffett
Alfred H
AH
Peacock
Munro
M
Miller
Paul D
PD
Lederman
Samuel N
SN
Chesnut
Charles H
CH
Lain
Douglas
D
Kivitz
Alan J
AJ
Holloway
Donna L
DL
Zhang
Charlie
C
Peterson
Mark C
MC
Bekker
Pirow J
PJ
D019386:Alendronate / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016723:Bone Remodeling / Q000187:drug effects; D001862:Bone Resorption / Q000097:blood / Q000188:drug therapy; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D000069448:Denosumab; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000503:physiopathology; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D050071:Bone Density Conservation Agents; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D000069448:Denosumab; D019386:Alendronate