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Odanacatib: a Possible New Therapeutic Option for the Treatment of Osteoporosis

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Odanacatib: a Possible New Therapeutic Option for the Treatment of Osteoporosis Drug Evaluation Odanacatib: a possible new therapeutic option for the treatment of osteoporosis Cathepsin K is a protease released by osteoclasts, which is involved in the destruction of collagen fibers that form the organic phase of the bone matrix, and plays a key role in bone resorption. Odanacatib is a selective inhibitor of cathepsin K, which blocks bone remodeling by inhibiting resorption. Phase II trials have shown that odanacatib is a potent antiresorptive agent and does not significantly reduce biochemical markers of bone formation during long-term treatment of postmenopausal women. This increases the bone mineral density that is comparable with the most powerful antiresorptive agents. Odanacatib has a generally favorable tolerability and safety profile. Currently, only Phase II studies have been reported and its efficacy in reducing fractures has not been demonstrated. The adverse effects are reversible and disappear after discontinuation. If this antifracture efficacy can be shown, odanacatib could be a safe, efficacious option for the treatment of osteoporosis. KEYWORDS: cathepsin K n odanacatib n osteoclast n osteoporosis José Luis Pérez-Castrillón*1,2, Florentino Pinacho3, Throughout life, bone remodeling maintains the gene that codes for cathepsin K, causing an Marta Ruiz-Mambrilla4 the structure of bone tissue, leading to changes increase in BMD, low stature, cranial deformi- & Antonio Dueñas Laita3 in bone density, shape and strength that allow ties and acroosteolysis of the distal phalanges 1Internal Medicine Department, it to adapt to biomechanical circumstances at [4]. In addition to osteoclasts, osteocytes secrete Rio Hortega University Hospital, Faculty of Medicine, Valladolid, Spain any given time. This remodeling occurs both in cathepsin K, although their function remains 2Institute of Endocrinology & Nutrition cortical bone, which is responsible for load bear- unknown. Research Support Unit. Rio Hortega ing, and in trabecular bone, which participates in Cathepsin K is a lysosomal protease that University Hospital, Faculty of Medicine, Valladolid, Spain the regulation of mineral homeostasis and bone belongs to the papain-like cysteine protease 3Clinical Pharmacology Service, strength. Bone remodeling consists of an initial family, which is coded by a gene located on Rio Hortega University Hospital, Valladolid, Spain phase of bone resorption followed by a phase of chromosome 1q21. Its structure is formed of 4Medical Center of Rehabilitation formation, both of which are regulated by general an amino-terminal region of 15 amino acids, & Language, Valladolid, Spain *Author for correspondence: [1] (endocrine) and local (paracrine) factors . a propeptide of 99 amino acids and a catalytic Tel.: +34 983420400 Osteoclasts are the key element in bone unit of 215 amino acids. The gene can be stimu- Fax: +34 983331566 resorption. Osteoclasts are derived from the lated by various factors, mainly bone-resorption [email protected] mononuclear phagocyte system, and their pro- stimulating cytokines [5,6]. liferation and maturation is stimulated by a pro- At present, there are no available data on the tein, RANKL, whose blockade is a therapeutic antifracture efficacy of odanacatib. Therefore, target in osteoporosis. Once mature, osteoclasts the objective of this article is limited to sum- bond to the bone surface via actin-rich podo- marizing the results of preclinical and clinical somes, forming cavities known as resorption studies on the effectiveness of odanacatib. lacunae. The secretion of protons by the cell Osteoporosis is a disease of bone remodeling, creates an acid medium within the lacunae, with resorption predominating over formation, which destroys the mineral phase of bone; the causing an imbalance. Thus, it seems reason- calcium hydroxyapatite crystals. Subsequently, able to use drugs that inhibit bone resorption the osteoclasts secrete cathepsin K, which dis- to correct this imbalance. Among the possible solves the organic component of the bone matrix therapeutic targets, cathepsin K inhibition is (consisting mainly of collagen) [2]. Cathepsin K attractive, since it inhibits destruction of the was first identified by Tezukaet al. using a differ- organic component of the bone matrix without entiation screening method [3]. The relationship affecting osteoclasts, either quantitatively or between cathepsin K and bone mineral density qualitatively. This has led to the development of (BMD) is confirmed by findings in a rare human drugs that inhibit cathepsin K and to the evalua- osteopetrotic disease, pycnodysostosis, in which tion of their efficacy and safety in the treatment loss of function is secondary to mutations in of osteoporosis. part of 10.2217/IJR.12.33 © 2012 Future Medicine Ltd Int. J. Clin. Rheumatol. (2012) 7(4), 369–376 ISSN 1758-4272 369 Drug Evaluation Pérez-Castrillón, Pinacho, Ruiz-Mambrilla & Dueñas Laita Odanacatib: a possible new therapeutic option for the treatment of osteoporosis Drug Evaluation Odanacatib clinical development and histomorphometric studies at the lumbar The efficacy and safety of various cathepsin K spine and hip in ovariectomized monkeys. In inhibitors, a new class of antiresorptive drugs, one study, 42 female rhesus monkeys (Macaca have been studied. Some potential agents were mulatta) aged 13–23 years were administered retired during Phase II clinical studies owing two doses of odanacatib at exposures below or to the appearance of severe dermatological similar to those subsequently used in the human side effects. Odanacatib is a powerful, selec- Phase III trial [13,14]. An increase in BMD and tive inhibitor of cathepsin K that blocks the bone turnover was observed in the lumbar spine proteolytic activity of the enzyme. Its chemical for both dosages used. There were differences in structure contains a phenyl ring that substitutes the biomechanical properties of bone between the P2–P3 amide bond of a amino acetronile control monkeys and treated ovariectomized dipeptide 1. Its potency and selectivity are due to monkeys. Interestingly, odanacatib affected the presence of the 4-fluoroleucine side chain at TRAP-5b, a marker of resorption, which also the P2 position interacting within the S2 pocket reflects the number of osteoclasts. This marker [7]. As it is selective, dermatological side effects remained stable during the length of the trial, have not been observed as it does not inhibit indicating that there was no reduction in the other types of cathepsin located in the skin [8] number of osteoclasts. that cause adverse cutaneous effects [9]. An increase in BMD was observed at the hip, Drug development consists of two main with increased cortical thickness reflecting the phases: preclinical trials in animals and clinical reduction of bone resorption at this level. This trials in patients and healthy volunteers. was accompanied by increased bone formation in the periosteum, which increased the diameter Preclinical phase of the femoral neck and resistance to fractures. Several experimental studies have examined the Thus, experimental studies show that possible role of cathepsin K in bone remodel- odanacatib can increase BMD at the hip and ing and, therefore, as a therapeutic target. The lumbar spine, blocking bone resorption in first studies were carried out in cathepsin gene ovariectomized animals while maintaining the knockout mice and found that osteoperosis was biomechanical properties of bone. Notably, the associated with a reduction in bone resorption. number of osteoclasts remained stable and, in Pennypacker et al. found an increase in cortical the hip, there was increased periosteal bone for- and trabecular bone volume, with an increase in mation and preserved endocortical formation, the number and thickness of trabeculae in the leading to an increase in femoral neck bone distal femur in a group of homozygote cathep- strength, resulting in a reduction in fractures. sin K-null mice [10]. Moreover, transgenic mice overexpressing cathepsin K had a lower BMD Phase I study associated with increased bone remodeling [11]. Phase I studies are aimed at determining the However, this model is not adequate to assess the pharmacokinetic and pharmacodynamic prop- efficacy of cathepsin K inhibitors intended to be erties of the drug, testing for safety and toler- used in humans, due to the low homology in the ability, and calculating dosages and dosing active form of the enzyme between humans and schedules. They are typically conducted in rodents. Models using rabbits and, especially, healthy volunteers and usually include a sam- monkeys, are preferable. ple size of 30–60 individuals in a given study. In an ovariectomized rabbit model, odana- In the case of odanacatib, the literature reports catib administered for 27 weeks was compared a study performed to evaluate the efficacy and with placebo and alendronate. Odanacatib safety of daily and weekly doses of odanacatib prevented estrogen deficiency-related bone loss administered to characterize the pharmaco- at the lumbar spine as alendronate. The non- kinetics and pharmacodynamics of the drug. ovariectomized rabbits showed the same bone The study population included 79 postmeno- mineral density. BMD increased in a dose- pausal women, whose hormonal situation was dependent manner in the total hip and femoral defined as the absence of menstruation during neck. Interestingly, bone formation was main- the previous 3 years or the previous year with tained in all sites analyzed and the biomechani- confirmation of an elevated follicle
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