MD Conference Express - ENDO 2015 - (Page 22)

SElECTED UPDATES 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. www.mdce.sagepub.com http://mdce.sagepub.com

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MD Conference Express - ENDO 2015