Emerging treatments for postmenopausal osteoporosis - focus on denosumab

Abstract

The pathway of the receptor activator of the nuclear factor kappaB ligand (RANKL), RANK and osteoprotegerin (OPG) plays a central role in coupling bone formation and resorption during normal bone turnover and in a wide spectrum of diseases characterized by disturbed bone remodeling, increased bone resorption and bone destruction (osteoporosis, Paget's disease of bone, rheumatoid arthritis [RA], metastatic bone disease). Clinical trials indicate that denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is effective in suppressing bone resorption, resulting in increase in bone mineral density (BMD) in post-menopausal women with low BMD, and has the potential to prevent progression of erosions in RA and of skeletal-related events in metastatic bone disease. The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM study. In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which until now have been available up to 4 years, but data on long-term safety will be needed.

Keywords: bone mineral density; denosumab; postmenopausal osteoporosis.

Figure 1

Free RANKL (ie, not bound by osteoprotegerin [OPG]) binds to the transmembrane RANK receptor, which upregulates intracellular signal transducers which are involved in cytoskeletal organization, cell motility, growth and survival, and some also bind NF κB. After ubiquitination, signal transducers are released from NF κB and degraded by proteasomes. NF κB can than migrate to the nucleus, were it upregulates transcriptional regulators that start osteoclastogenic gene transcription.

Figure 2

Phase 2 study of denosumab every 6 months in postmenopausal women with low (bone mineral density) BMD: lumbar spine, total hip, and distal 1/3 radius BMD at 12 months. Adapted from J Bone Miner Res. 2007;22:1832–1841, with permission of the American Society for Bone and Mineral Research; and from N Engl J Med. 2006;354:821–831.

Figure 3

Effect of 4 years of denosumab every 6 months on lumbar spine (LS) bone mineral density. Adapted from J Bone Miner Res. 2007;22:1832–1841, with permission of the American Society for Bone and Mineral Research.

Figure 4

Effect of denosumab re-treatment and changes to lumbar spine (LS) and total hip bone mineral density. Reproduced with permission from Miller PD, Bolognese MA, Lewiecki EM, et al. Amg Bone Loss Study Group. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone. 2008;43(2):222–229. Copyright © 2008 Elsevier.

Figure 5

Effect of denusomab vs alendronate head to head trial on bone markers. Reproduced from J Bone Miner Res. 2009;24:153–161, with permission of the American Society for Bone and Mineral Research. Notes: ^asignificantly different from alendronate, p ≤ 0.0001.