Denosumab: mechanism of action and clinical outcomes

Abstract

Aims: To describe the mechanisms of action of denosumab, a novel antiresorptive agent, contrasting it with other antiresorptive and anabolic osteoporosis treatments.

Methods: Published papers related to the mechanism of action of approved osteoporosis treatments were sought through MEDLINE searches.

Findings: Osteoporotic fractures carry a substantial burden of morbidity and mortality, but pharmacotherapy can prevent such fractures in high-risk individuals. Antiresorptive drugs (e.g. bisphosphonates, oestrogen, denosumab) reduce bone turnover by distinct mechanisms. Denosumab, a recently approved therapy, is a fully human monoclonal antibody that binds the cytokine RANKL (receptor activator of NFκB ligand), an essential factor initiating bone turnover. RANKL inhibition blocks osteoclast maturation, function and survival, thus reducing bone resorption. In contrast, bisphosphonates bind bone mineral, where they are absorbed by mature osteoclasts, inducing osteoclast apoptosis and suppressing resorption. These differences in mechanism influence both the onset and reversibility of treatment.

Discussion: Effective pharmacotherapy is necessary for patients at high risk of fracture. Among the treatment options for postmenopausal osteoporosis, there are significant differences in mechanism and dosing. Denosumab acts by a novel mechanism and is administered twice yearly by subcutaneous injection. Identified by Osteoporosis Canada Clinical Practice Guidelines as a first-line agent for treatment of postmenopausal osteoporosis, denosumab represents an important addition to our treatment options.

Figure 1

Resorption of old bone matrix and deposition of mineral into new bone are linked. Osteocytes, osteoblasts and osteoclasts are the main cells of the BMU of remodelling bone. BMUs like the one depicted here occur by the millions throughout the skeleton. They carry out the sequential resorption of old bone matrix and deposition/mineralisation of new bone. Osteocytes form a network of interconnected cells occupying lacunae (pits) within the mineralised bone tissue. Osteocytes are derived from osteoblasts (bone-forming cells) that were buried as new bone tissue formed, and they direct bone remodelling in response to mechanical strain and other stimuli. Osteocytes and osteoblasts initiate bone remodelling and start the process of bone resorption by releasing RANKL, which binds to RANK on osteoclasts and osteoclast precursors, activating these cells. Osteoblasts also produce OPG, which suppresses bone turnover. OPG binds to RANKL, preventing it from interacting with RANK. Activation of bone remodelling in a BMU therefore depends on the balance between RANKL and OPG. Adapted from, with permission of John Wiley & Sons, from Denosumab: Mechanism of Action and Clinical Outcomes, Sundeep Khosla, Jennifer J Westendorf, Merry Jo Oursler, 118, 2, 2008; permission conveyed through Copyright Clearance Center Inc.

Figure 2

Sites of action for first-line osteoporosis treatments. Teriparatide, a recombinant fragment of parathyroid hormone, stimulates bone formation by increasing osteoblast activity and, to a lesser extent, inhibiting osteoclast recruitment. All other approaches shown here are antiresorptive, reducing bone turnover by targeting osteoclasts. Estrogen replacement therapy and likewise the SERM raloxifene interfere with various osteoblast-derived factors that stimulate osteoclasts (e.g. IGF1, TGF-β and TNF-α). Denosumab binds the cytokine RANKL, preventing it from binding its receptor, RANK. Like OPG (see Figure 1), denosumab prevents maturation of osteoclast precursors and promotes apoptosis of mature, multinucleated osteoclasts. Bisphosphonates bind to bone mineral and are taken up by osteoclasts, causing them to undergo apoptosis or have reduced resorptive capacity. When osteoclast number and activity decline, bone formation eventually slows to maintain a balance of bone resorption and formation

Figure 3

Effect of denosumab treatment discontinuation and reinitiation on bone mineral density in the lumbar spine (A) and total hip (B). Subjects were randomised to denosumab 30 mg Q3M or placebo twice yearly or, on an open-label basis, to alendronate once weekly. Denosumab subjects were transitioned to placebo at Month 24, with their last active treatment at Month 21; they reinitiated active treatment at Month 36 with the 60 mg Q6M dose. Alendronate subjects discontinued treatment at Month 24 and were observed until Month 48. Denosumab’s effects were fully reversible at the hip and lumbar spine and were restored upon retreatment. Placebo-treated patients showed a consistent loss of BMD throughout the study period, affecting both sites. Patients treated with alendronate who subsequently stopped treatment showed little change in BMD at the lumbar spine, but larger decreases in hip BMD. Adapted from Miller et al., 2008 (22). Reprinted from Denosumab: Mechanism of action and clinical outcomes, 43, 2, Paul D. Miller, Michael A. Bolognese, E. Michael Lewiecki, Michael R. McClung, Beiying Ding, Matthew Austin, Yu Liu, Javier San Martin, for the AMG 162 Bone Loss Study Group, 222–229., 2008, with permission from Elsevier.