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Targeting Cathepsin K for the Treatment of Osteoporosis – Focus

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Targeting Cathepsin K for the Treatment of Osteoporosis – Focus Drugs or :he Future 2010, 35(8): 643-,;49 THOMSON Rf.CJTfRS \' (opvtlght ~ lOIO Prous Sd1.?no:•, SA U. <11 it~ lir.f:>nsor!=. At~ right~ r~~Q1~d CCC: 0.377-Lll82/W10 001: 10 1353/~of.2010 35 8 .152~'l'.2 F{E\/!EW J\f<TICLE TARGETING CATHEPSIN K FOR THE TREATMENT OF OSTEOPOROSIS: FOCUS ON ODANACATIB E.M. Lewiecki New Mexico Clinical Research & Osteoporosis Center, Albuquerque, New Mexico, USA CONTENTS density (BMD) and bone strength are stable. II bone resorption SummJry .......... ....... .. , . .... ..... • ...... ... .643 exceeds bone formation, as occurs in postmenopausat estrogen· deficient women, there is a net loss of bone over time that may ulti· Introduction ........ ........ • .. .... .. • ..... ..... .. .643 mately result in osteoporosis and increased risk of fractures (1) . Cathepsin K inhibitors .......... .. ...... .. .... ... .... .645 Osteoporosis is a common disease associated with increased Conclusions ....... ....... .. .. .. ...... ....... .648 morbidity, increased mortality and high henlthcare costs due to frac­ Referencr.s .......... ..•. .. .... ... • . ... • .. .. , .. .648 tures (2). Bone resorption requires the attachment of an osteoclast to the bone surface by means of a "sealing zone" in order to create a self· SUMMARY contained compartment between the bone surface and the adjacent Cathepsin K is a lysosomal cysteine protease expressed by osteoclasts ruffled border of the osteoclast (3). The acidic microenvironment that degrades type I collagen during the process of bone remodeling. beneath the osteoclast demineralizes the bone and exposes the Postmenopovsal osteoporosis (PMO) is a disease of excessive bone underlylng matrix, which is then degraded through the action of cys­ tvrnover, wit/1 an imbalance between bone resorption and bone formo - teine proteases (4). Since cathepsin K is the most abundant cysteine tion that covses loss of bone strength and increased risk of fractures. protease expressed in osteoctasts and a rate-limiting factor for Medications that reduce bone turnover hove been proven to reduce osteoclastic bone resorption (5), it has been identified as a potential fracture risk in women with PMO. Inhibition of cathepsin K reduces target for the treatment of diseases associated with high bone bone resorption, with the potential ofdecreasing fracture risk in women resorption (6·8), such as postmenopausal osteoporosis (PMO). with PMO. Odanacatib (MK-0822, MK-822) is an orally administered Cathepsin K and other cysteine proteases are secreted as inactive cothepsin K inhibitor that is currently in development for the treatment enz.ymes that require acidic conditions. as exist beneath osteoclasts of osteopo,osis. In a phase II clinical trial orol odonacatib increased attached to the bone surface (Fig. l), for cleavage of the propeptide bone mineral density (BMD) and reduced bone turnover markers more to form the active enzyme. Cathepsin K degrades type l collagen in than placebo in postrilenopousal women with low BMD, with no the telopeptide regions, as well as at multiple locations on the triple reports ofintolerance or skeletal toxicity. A p/1ase Ill clinical trial to eval· helix. uate the effects of odanocatib on fracture risk in women with PMO is The rationale for the clinical development of inhibitors of cathepsin currently under way and fully enrolled. Odanacatib is a promising K to treat osteoporosis is supported by animal studies. For example, emerging agent for the management of PMO and other skeletal disor· there is evidence that cathepsin K knockout mice have increased ders ossocioted with·excessive bone turnover. BMD, t11ickened bone trabeculae and increased bone strength (9); transgenic mice with overexpression of cathepsin K have reduced INTRODUCTION trabecular bone volume due to accelerated bone turnover (lO); com· Bone remodeling is a physiological process by which the adult skele· pounds that inhibit cathepsin K reduce markers of bone resorption in ton continually renews itself. Removal of small discrete packets of ovariectomized (OVX) nonhuman primates (11) and increase BMD in bon!:! collagen and mineral occurs tl1rough the action of osteoclasts OVX rabbits (12). (bone-resorbing cells), followed by deposition of new collagen by Cathepsin K deficiency in humans occurs in a rare autosomal reces· osteoblasts (bone-forming cells) and subsequent mineralization of sive disorder called pycnodysostosis (13), thought to be present in the collagen. When bone resorption and formation are well bal· the well-known 19e1, century French artist Henri Toulouse·Lautrec anced, as typically occurs in healthy young adults, bone mineral (14). Individuals with pycnodysostosis have short stature and dense bones (pycnos = dense), but typically sufter from low trauma frac· tures, while those who are heterozygous for this mutation are cllni· Co1-respondenc.i: E.M. Lewiecki, MD, FACP, FACE. NP.w Mexico Clini(al Rese~l'Ch & Osteoporo5i~ Center, 300 O~k 51., NE All>tJqu~rque, NM 87106, USA. E·mail: LEWIECKI@ cally normal (15). It has been suggested that skeletal fragility asso· aolcom, ciated with pycnodysostosis may be the result of a profound (j4~ CATHF.PSfN K INHIBITION FOR OSTF.OPOROSJS E.M. Lewierki ., .-~--- --·- ~·---·-- ------ ... ,:. · a,~i lntegrin ' ·:,~"l(-·~.. Lysosomes er ..... ........ Cat K .. ... __ __~ ~M CIC-7 ,_.. j, V-ATPase : N RANK/RAN KL er Calcitonin & Receptor N co, • enzymes pH=S • • Cathepsin K /0 _-z.,,, .... Bone • • "(\.. I\ A : •• I" JV" • ,/ . .. / ~ :~.-.:: :. :: .::·...... ~.~-~ ,,, ' •, ~ , ...• .•. -!• -~--- -· .... Figure 1. Schematic representation of a resorbing osteoclast. Demineralization is the result of acidification of the resorption lacuna due to secretion of wand et· ions. Secreted lysosomal cathepsin K degrades type I collagen through cleavage of the N-terminal region and the triple helical structu1·e of collagen mol· ecules at multiple sites. From Rodan, S.8., Duong, L.T. Cothepsin K -a new molecular target for ostP.opomsis, IBMS BoneKEy. 2008 January;S(l):16·24, wltl1 per­ mission from the International Bone & Mineral Society. decrease in bone remodeling, leading to a lack of microdamage risk (22) and greater healthcare costs (23) than those with good removal, although there is no direct evidence for microdamage compliance and persistence. There are many factors contributing to accumulation (16). Others have suggested that the increased sus­ patients not taking medication correctly or sufficiently long to bene­ ceptibility to fr;ir.tures in these patients is due to osteomalacla tl1at fit (?.4). Among these are side effects of trPMrnr.nt or the feM of side occurs concomitantly with increased BMD (17), similar to rickets, effects that have not actually occurred. Oral bisphosphonates may which has been paradoxically reported in patients with infantile cause upper gastrointestinal upset and intravenous bisphospho­ malignant osleopetrosis (18}. nates sometimes cause transient flu-like symptoms. Other events reported with bisphosphonate use, without clear evidence of a A compound that rPrllJC"f!S but does'not eliminate cathepsin K might be expected to act as an anti resorptive c'.lgent with potentially bene· causal relr1tionship or well-defined patl1ogenesis, include ficiat skeletal effects. Antiresorptive agents that are currently osteonecrosis of the jaw, atypical femur fractures, chronic muscu­ approved for the manc'.lgement of PMO include four bisphospho­ loskeletal pain and atrial fibrillation (25). Tl1ere have been theoreti­ nates (alendronate, risedronate, ibandronate, zoledronate), deno­ cal concerns, without clec'.lr evidence of increased risk, over possible sumab, rnloxifene and nasal calcitonin. These .igents have been adverse immune effects with denosumab (26), a fully human mono­ shown to reduce bone resorption marker levels, stabilize or increase clonal antibody to receptor activator of nuclear factor kappa-B lig BMD, and reduce fracture risk. Despite proven efficacy and general­ and {RANKL), il cytokine member of the tumor necrosis factor (TNF) ly favorable safety protiles, their impact in reducing the burden of family tl1at is the principal mediator of osteoclastic bone resorption . osteoporotic fractures has been disappointing (19) due to subopti · Raloxifene, a selective estrogen receptor modulator, may cause leg mal compliance and persistence (20). Patients with poor compliance cramps, vasomotor symptoms and thromboembolic events, and .:ind pcrsistP.nce have a reduced BMD response (21), hi4:JhP1' frr1rt1m• increilse the risk of fatal stroke in womPn ,:it high risk for cardiovas- 644 THOMSON Hf.UTHlS - 01\JQS or th~ rutll(P. <'010, 35(!1) E.M. L,wie,ki CATHEPSIN K INHIBJ rlON FOR OSTEOP0110SIS cular disease (27). Nasal calcitonin is generally well tolerated except implicated in the pathogenesis of osteoarthritis, with the finding of for nasal irritation and epistaxis in some patients (28). but appears accumulation of this enzyme in articular chondrocytes in a trans­ to have the weakest antiresorptive effect of all approved agents. For genic mouse model (38). Catl1epsin K may play a role in the progres­ all these reasons, there may be clinical utility in developing new sion of atherosclerosis, suggesting that inhibition of cathepsin K therapeutic agents that expand the options for managing osteo­ might be beneficial for its treatment {39). Cathepsin K is upregulat­ porosis, with the hope of providing more choices for matching the ed in human tumor cells. including breast, tung, brain, bone, risk/benefit profile of the drug with the
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