Denosumab is a human monoclonal antibody which specifically blocks receptor 
activator of nuclear factor κB ligand and is a very potent antiresorptive drug. 
Its efficacy in reducing the risk of vertebral, hip and nonskeletal fracture has 
been proven in a large prospective, randomized multicenter study of 7808 
postmenopausal women with osteoporosis [Fracture Reduction Evaluation of 
Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial]. Denosumab causes 
somewhat greater increases in bone mineral density (BMD) than the class of 
bisphosphonate antiresorptives. Denosumab also causes an increase in bone mass 
and bone strength in the spine, ultradistal and diaphysis of the radius, 
proximal tibia and the hip. Recently long-term treatment with denosumab has been 
shown to cause a continued almost linear increase in total hip and femoral neck 
BMD beyond 3 years up to 8 years. In this respect, denosumab seems to differ 
from the bisphosphonate group in which the rate of improvement of BMD diminishes 
and for some drugs becomes negative after 3-4 years when the process of 
secondary mineralization flattens out. This unique property of an antiresorptive 
drug points towards mechanisms of action which differ from the bisphosphonate 
group. Both types of antiresorptives decrease cortical porosity but contrary to 
bisphosphonates the reduction in cortical porosity continues with denosumab 
which, in addition, also seems to cause a slight continuous modeling-based 
formation of new bone despite suppression of bone remodeling. The net effect is 
an increase in cortical thickening and bone mass, and increased strength of 
cortical bone. This may contribute substantially to the significant further 
reduction of the nonvertebral fracture risk which was found in the long-term 
denosumab arm of the FREEDOM extension trial during years 4-7.