Receptor activator of NF-kappaB ligand (RANKL) is a member of the tumor necrosis factor (TNF) family of cytokines that is produced by cells of osteoblastic lineage, and its cellular receptor RANK is present on the surface of hematopoietic osteoclast precursor cells as well as on mature osteoclasts. RANKL is now known to be the common and requisite factor intervening in osteoclast formation in response to all known catalysts. As such, the RANK/RANKL/osteoprotegerin pathway is essential for the process of osteoclastogenesis and modulates the differentiation, activation and survival of osteoclasts, thereby regulating bone resorption. Compounds acting on this pathway are being actively investigated for the treatment of osteoporosis (Integrity Disease Briefings: Osteoporosis [consulted May 28, 2009]).

Several preclinical and clinical studies of the RANKL inhibitor denosumab (Amgen), a fully humanized monoclonal antibody to RANKL, were presented at the 36th European Symposium on Calcified Tissues, celebrated in late May in Vienna.

A nonhuman primate study demonstrated the safety and efficacy of changing from alendronate to denosumab treatment: ovariectomized cynomolgus monkeys were treated for 6 months with vehicle or alendronate and then switched to denosumab. The transition was safe and while serum CTx and osteocalcin were reduced with denosumab and alendronate alone, further reductions were seen after the transition. Dynamic histomorphometry also showed greater reductions in bone turnover parameters at trabecular and cortical sites with denosumab alone or in animals switched from alendronate to denosumab compared to those given alendronate alone. Cortical and trabecular bone mass and strength were maintained or improved after treatment transition (Ominsky, M.S. et al. 36th Eur Symp Calcif Tissues (ECTS) (May 23-27, Vienna) 2009, Abst P483).

In a double-blind, phase II study, 247 postmenopausal women with low bone mass were randomized to placebo, denosumab 60 mg twice yearly or alendronate 70 mg weekly p.o. and given daily calcium and vitamin D. High-resolution peripheral quantitative computed tomography assessment of the ultradistal radius showed increased total bone mineral density (BMD) at 6 and 12 months with denosumab, while alendronate reduced the BMD loss seen in the placebo group (Seeman, E. et al. 36th Eur Symp Calcif Tissues (ECTS) (May 23-27, Vienna) 2009, Abst OP14). In another double-blind study, 504 postmenopausal women with low bone mass received alendronate 70 mg weekly for 6 months and then continued that therapy or were transitioned to s.c. denosumab 60 mg every 6 months. Transition to denosumab was associated with greater increases in BMD at the total hip and lumbar spine as compared to continued alendronate, and the greatest increases were seen in patients with the highest levels of baseline bone turnover (Roux, C. et al. 36th Eur Symp Calcif Tissues (ECTS) (May 23-27, Vienna) 2009, Abst P476).

Amgen has filed a BLA for denosumab in the U.S., where the proposed indication is the treatment and prevention of postmenopausal osteoporosis and treatment and prevention of bone loss in patients undergoing hormone ablation therapy for either prostate or breast cancer. The FDA has accepted the submission and has set a Prescription Drug User Fee Act action date for the application of October 2009. Amgen has also submitted marketing applications for use of denosumab for these indications in the E.U., Canada, Switzerland and Australia. Assuming approval is granted, denosumab will become the first-in-class member of this promising new class of antiosteoporosis agents.