MD Conference Express - ENDO 2015 - (Page 22)
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Table 3. Comparison of Effects of RANKL Inhibition and Cathepsin K Inhibition
RANKL Inhibition (Denosumab)
Cathepsin K Inhibition (Odanacatib)
Target cell
Osteoclast
Osteoclast + osteocyte
Effect
Blocks differentiation
Blocks function
Bone-remodeling activation frequency
Very low
Normal
Bone matrix turnover
Very low
Low
Remodeling-based formation
Very low
Normal
Cortical porosity
Decreased
Decreased
Cortical thickness
Increased (endosteum)
Increased (endosteum + periosteum)
RANKL, receptor-activated nuclear factor κB ligand.
Reproduced with permission from MR McClung, MD.
as bone anabolic agents for the treatment of osteoporosis in postmenopausal women. The preliminary results
of surrogate end points such as BMD and bone markers
are promising and associated with a good safety profile.
Antifracture efficacy data should be available soon for
romosozumab. Further studies are needed to integrate
this new treatment option within current osteoporosis
therapies.
Michael R. McClung, MD, Oregon Osteoporosis Center,
Portland, Oregon, USA, focused on the osteoclastosteoblast coupling mechanism to demonstrate the
different effects of receptor-activated nuclear factor κB
ligand (RANKL) and cathepsin K inhibition on bone
remodeling. Coupled bone remodeling involves communication between osteoblasts and osteoclasts via
the RANKL pathway [Sims NA, Martin TJ. Bonekey Rep.
2014]. RANKL is a growth-promoting factor secreted
by osteoblasts that binds to its receptor, RANK, on preosteoclasts, resulting in differentiation and proliferation
of osteoclasts. Osteoclasts modulate osteoblast activity
by releasing regulatory factors from bone matrix during bone resorption. The RANKL inhibitor, denosumab,
causes a marked decrease in osteoclasts, resulting in
reduced bone resorption, followed by a substantial
decrease in bone formation.
Cathepsin K, a specialized enzyme highly expressed in
osteoclasts, is the main proteolytic enzyme that degrades
proteins in bone matrix. Cathepsin K inhibition results
in decreased bone resorption but osteoclast number and
function are not decreased and may increase, resulting in
no change in or increased bone formation. Odanacatib
is a highly selective, reversible, and potent inhibitor
of cathepsin K [Duong LT. Bonekey Rep. 2012; Leung P
et al. Bone. 2011]. In a phase 2 study, odanacatib administered for 5 years to postmenopausal women with low
22
May 2015
BMD reduced markers of bone resorption, while bone
formation markers fell at the outset of treatments but
returned to baseline after 2 years. As a consequence, progressive increases in spine and hip BMD were observed
[Langdahl B et al. J Bone Miner Res. 2012].
The just-completed phase 3 LOFT trial [McClung MR
et al. ASBMR 2014 (abstr 1147)] of odanacatib in 16 000
postmenopausal women with osteoporosis was stopped
at the first interim analysis because of robust efficacy.
The trial design has been published [Bone HG et al.
Osteoporos Int. 2015], but unpublished results show that
over about 3 years, odanacatib reduced vertebral fractures by 54%, hip fractures by 47%, and clinical vertebral
fractures by 72%. The longer patients were on therapy,
the greater the apparent reduction in nonvertebral fracture risk.
Table 3 compares the effects of RANKL (denosumab)
and cathepsin K (odanacatib) inhibition.
Cathepsin K inhibition is a potential new therapy for
osteoporosis with a unique mechanism of action that
inhibits bone resorption but preserves osteoclast function and bone formation. Dr McClung concluded that
odanacatib promises to be a useful and important addition to treatment options for osteoporosis.
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