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Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis
Aline G. Costa, Natalie E. Cusano, Barbara C. Silva, Serge Cremers and John P. Bilezikian
Abstract | Bone remodeling consists of two phases—bone resorption and bone formation—that are normally balanced. When bone resorption exceeds bone formation, pathologic processes, such as osteoporosis, can result. Cathepsin K is a member of the papain family of cysteine proteases that is highly expressed by activated osteoclasts. Cathepsin K readily degrades type I collagen, the major component of the organic bone matrix. With such a major role in the initial process of bone resorption, cathepsin K has become a therapeutic target in osteoporosis. The antiresorptive properties of cathepsin K inhibitors have been studied in phase I and phase II clinical trials. Phase III studies are currently underway for odanacatib, a selective cathepsin K inhibitor.
Costa, A. G. et al. Nat. Rev. Rheumatol. 7, 447–456 (2011); published online 14 June 2011; doi:10.1038/nrrheum.2011.77

The human skeleton is in a constant state of remodeling, a dynamic process consisting of two normally balanced phases of bone resorption and bone formation. Initiating the process of bone remodeling is the resorption of a micropacket of bone, which is carried out by the osteoclast, a multinucleated cell with monocyte/macrophage lineage. After a 3–5 week period of osteoclast-mediated bone resorption at a site that becomes defined as the ‘bone remodeling unit’, bone formation begins. The cell responsible for bone formation is the osteoblast, a uni­ nuclear cell that synthesizes and secretes type I collagen at the site of bone resorption. When these two processes are balanced, bone is renewed, but is neither gained nor lost. In the adult skeleton, it is more likely that an im­ balance exists between these two processes. Bone resorption predominates over bone formation when osteoclasts are too active (typically the case in an estrogen-deficient, early postmenopausal woman) or when osteoblasts are not active enough, or, more likely, through a combination of overactive osteoclasts and underactive osteoblasts. Bone loss ensues. Along with the loss of skeletal mass, a deterior­ation of skeletal microstructure and an increased risk of fragility fracture are observed. Much more rarely, the osteoclast can be dysfunctional, a situation that would lead to increased bone mass. Cathepsin K, a protease that belongs to the papain family of cysteine proteases and is highly expressed by the osteoclast, is encoded by the cathepsin K gene (CTSK). Cathepsin K is secreted from the osteoclast into a microenvironment defined by a space called the ‘sealing zone’. The ruffled membrane—the resorptive organelle of the osteoclast—is in direct contact with the sealing zone and is responsible for acidifying this isolated compartment to a pH of approximately 4.5. This acidified milieu
Competing interests The authors declare no competing interests.

dissolves the mineralized component of bone, exposing its organic matrix, with subsequent degradation of type I collagen by cathepsin K and other proteases (Figure 1).1 With such a major role in the initial process of bone resorption, cathepsin K has long been considered as a potential target for disorders such as osteoporosis, in which reduced bone resorption has been documented to be a beneficial therapeutic mechanism. In this Review, we discuss the physiological and pathophysio­ logical functions of cathepsin K, and describe recent developments in the use of cathepsin K inhibitors for the treatment of osteoporosis.

Cathepsin K expression
The CTSK gene resides in the pericentric region of human chromosome 1. It spans approximately 12.1 kb, comprising 8 exons and 7 introns.2 Cathepsin K messenger RNA (mRNA) is highly expressed in osteoclasts, where the other cathepsins seem to be found in negligible, if any, quantities.3 The expression of cathepsin K is regulated by the receptor activator of nuclear factor κB ligand (RANKL), a critical inducer of osteoclastogenesis. In osteoclasts, RANKL activates NFATc1 (nuclear factor of activated T cells), which in turn stimulates the transcription of cathepsin K by directly interacting with the CTSK promoter. Disrupting Ca2+ signaling by blocking Ca2+ channels prevents RANKL from increasing CTSK expression in osteoclasts.4 Tumor necrosis factor (TNF) and many other agents capable of increasing osteoclast formation and differentiation, such as vitamin D, parathyroid hormone, and interleukins, can also stimulate cathepsin K expression.5 The inactive zymogenic form of cathepsin K predominates in quiescent osteoclasts that are distant from sites of active bone resorption, as assessed by cytochemical and specific immunostaining assays. It was previously thought that osteoclasts secreted the cathepsin K pro­ enzyme into the resorption lacunae, and that activation

Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 W. 168th Street, New York, NY 10032, USA (A. G. Costa, N. E. Cusano, B. C. Silva, S. Cremers, J. P. Bilezikian). Correspondence to: J. P . Bilezikian

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VOLUME 7  |  AUGUST 2011  |  447

tyrosine or glycine at the P1' position. therefore. has a fundamental role in bone resorption ■■ Loss-of-function mutations in the cathepsin K gene lead to pycnodysostosis. Activated osteoclasts express almost exclusively the mature cathepsin K molecule.21 Before the discovery of cathepsin K. a cysteine protease that is highly expressed in osteoclasts. therefore. cathepsin K. and B. and P1' positions of the substrate.7 Cathepsin K is not unique to the osteoclast: it has been found to be active and expressed—albeit in lower amounts—in the skin. All rights reserved . are secreted into this zone.23 Another study www. testis.19 Such biochemical markers have achieved clinical utility in tracking the pathological processes that increase bone resorption. This schematic depiction shows the sealing zone created by integrin αvβ3. are much less efficient. such as cysteine proteinases. heart. as a result. ovary. Cathepsin K has a broad. with optimal activity against native collagen at pH 6. MMP. Its expression in dermal fibroblasts17 and. lung.18 Serum and urinary markers that detect type I collagen telopeptide crosslinks from the N‑terminal and C‑terminal ends of the molecule are called NTX and CTX. therefore. and colon.22 Cathepsin K performs both actions.25 Cathepsin K releases the NTX epitope with 100% yield from type I collagen.14 and white adipose tissue (with higher levels noted in obese individuals). as shown in preclinical studies.15. and decreased bone turnover ■■ In preclinical studies. and a branched hydrophobic side chain. generating a variety of fragments in the 70–80 kDa weight range.13 macrophages and smooth muscle cells of atherosclerotic lesions. P1. 36%. as further detailed below. more-selective compounds currently in phase III trials ■■ Clinical trials have demonstrated that cathepsin K inhibitors are potent antiresorptive drugs that act exclusively on bone resorption without perturbing bone formation or osteoclast survival. skeletal muscle. a small or hydrophilic side chain at the P1 position. Local factors.9 The substrate specificities of the papain family of cysteine proteases are determined in large part by the amino acids occupying the P2. including phosphatidylinositol 3‑kinases. The matrix metalloproteinases (MMPs) and neutrophil serine elastase are able to cleave the triple helix across all three chains.12. Type I collagen fibers comprise a triple helix formed by one α2 and two α1 chains. may account for some of the adverse effects seen with cathepsin K inhibition in clinical trials. are able to cleave the telopeptide.0. it was thought that separate proteinases. small intestine. respectively. and for monitoring the response to thera­ peutic agents that reduce bone resorption. placenta. MMP-9. the lung. L. The osteoclast. and MMP-13.24 The preference for glycine at the P1' position makes cathepsin K readily able to degrade collagen helical domains. adheres to the bone. Only proteinases with broader HCO3– CI– Cath K H+ HCO3– CI– αvβ3 H+ CI– Bone Figure 1 | Mechanism of osteoclast-mediated bone resorption.20. The ends of the triple helix—the telopeptides— are cross-linked by pyridinoline and deoxypyridinoline. and demonstrate rapid reversibility Additional studies in human tissue report the expression of cathepsin K in osteoblasts. Hydrochloric acid and proteases. The cross-linked carboxyterminal telopeptide of type I collagen (1CTP) represents a larger fragment generated by collagenolysis. matrix metalloproteinase. Abbreviations: Cath K. this premise is no longer tenable in light of recent data that document the presence of immuno­ reactive. Cathepsin K preferentially cleaves substrates with a small or branched hydrophobic side chain at P2. a disorder characterized by osteosclerosis. Cathepsin K and bone resorption Approximately 90% of the organic matrix of bone is composed of type I collagen. although also active against type I collagen. bone fragility.REVIEWS Key points ■■ Cathepsin K. CTX represents a smaller breakdown product of 1CTP. mature cathep­sin K in osteoclasts that are closer to the bone surface. and. 8–10 448  |  AUGUST 2011  |  VOLUME 7  © 2011 Macmillan Publishers Limited. been implicated in a number of disorders that are not related to abnormal mineral metabolism. The breakdown products of type I collagen are sensitive measures of osteoclast-mediated bone resorption. Approximately 90% of the organic matrix of bone is composed of type I collagen.16 Cathepsin K has.nature. were required to fully degrade type I collagen.7 The in vivo activation of cathep­sin K from the 37 kDa procathepsin K molecule to the active 27 kDa enzyme. which leads to the degradation of the organic collagen matrix.6 However. bell-shaped pH activity profile. 23. degrades proteins present in the organic matrix of bone. including cathepsin K. cathepsin K inhibitors decreased bone resorption markers and prevented bone loss induced by ovariectomy ■■ The concerning off-target effects reported in early human clinical trials of cathepsin K inhibitors have not been observed with the newer. is thought to take place intracellularly in lysosomal compartments before its secretion into the resorption lacunae. as demon­ strated by high levels of enzyme activity polarized to the ruffled border of the cell. respectively. and involve approxi­ m ately 4% of the collagen molecule. are believed to regulate this process.11 breast and prostate cancer cells (both in the primary tumor and in skeletal metastases). with only 57%. and 27% of the yield of cathepsin K pro­ ducts. acting in a cooperative fashion. Cathepsins S. but are not able to attack the telopeptides. occurred extracellularly in the acidic microenvironment.

24 In addition.40.60 evaluated the development of bleomycin-induced pulmonary fibrosis in cathepsin‑K-deficient mice compared with wild type animals.41 Sedano et al.33. which could be explained by some redundancy in collagenase activities in mouse osteoclasts. a gelatinase that is highly expressed in osteoclasts. micrognathia. knockout mice showed increased bone strength in the femoral midshaft and vertebral body compared with wild type animals. lower insulin levels. clavicular dysplasia. consistent with decreased bone turnover. it is still unclear whether cathepsin K deficiency has a beneficial or a detri­ mental effect on atherosclerotic plaque formation and stability.44 In addition.10 suggest that cathepsin K participates in the degradation of extracellular matrix of the lung. and fibronectin. but osteoclasts fail to resorb the organic bone matrix. when biomechanical tests were applied. as cathepsin K degrades this bone growth factor during the process of bone resorption.57. Marouteaux and Lamy 38 speculated that the French painter Henri de ToulouseLautrec had pycnodysostosis. 36. Pycnodysostosis is generally diagnosed during childhood in the setting of the characteristic physical features and a history of multiple fractures.47–49 Osteoclast numbers and bone demineralization are normal. given his history of short stature.40 Anemia and cranial nerve compression. bone biopsies of affected patients show severe osteosclerosis.39.55 Further studies indicated an effect of cathep­ sin K on atherosclerosis.52 Although individuals with pycnodysostosis have an increased fracture risk. acro-osteolysis of the distal phalanges. large amounts of undigested mineralized matrix. potentially favoring plaque stability. and improved glucose tolerance. In comparison. seem relatively unaffected.43 NTX and CTX levels are low in patients with pycnodysostosis. knockout mice have decreased plasma levels of tri­ glycerides and cholesterol.59 The role of cathepsin K in the pathogenesis of pulmonary fibrosis has also been examined in animal studies. overhanging nasal tip. augmented macrophage foam cell formation in atherosclerotic lesions has also been noticed.49 In fact.45.49 This finding might be explained by an increase in local ­ insulin-like growth factor 1 (IGF1) in the absence of cathep­sin K. Unexpectedly. the predominant protein in cartilage. solubilizes only 38% of the bone after 96 h. fractures with relatively mild trauma. 30–32 Additional studies in patients with pycnodysostosis have confirmed loss-of-function mutations in the CTSK gene.48 Whereas long bones and vertebrae display an osteopetrotic phenotype.38 The disorder is characterized by osteosclerosis and bone fragility with a high fracture risk.49–51 a fact explained by a recent study that showed a key role for this enzyme in osteoclast apoptosis and senescence. about 80% at 72 h.31. which could destabilize the plaque. and ostosis (bone). a rare syndrome of skeletal dys­ p lasia with autosomal recessive inheritance (OMIM 265800). such as rheumatoid arthritis and osteoarthritis.REVIEWS found that cathep­sin K was able to solubilize 40% of the collagen helix and telopeptides of adult cortical bone after 24 h of incubation. All rights reserved Pycnodysostosis The importance of cathepsin K function in skeletal homeostasis was first demonstrated in humans by the finding that mutations in the CTSK gene are responsible for pycnodysostosis.54. a recent study failed to show poor bone quality in 19-week-old cathepsin‑K-knockout mice.46 Cathepsin‑K-knockout mouse models The animal phenotype of pycnodysostosis is reproduced in mice by targeted deletion of cathepsin K.56.29 in cathepsin K develop increased trabecular and cortical bone mass due to impaired bone resorption. To address this question. a high bone-formation rate was also demonstrated in mice lacking cathepsin K. and a perturbation of the architecture of the trabeculae and the lamellar arrangement of collagen fibrils. including osteonectin. Also. and dental abnormalities. reduced stature. MMP‑9. Mice deficient NATURE REVIEWS | RHEUMATOLOGY .27 The role of cathepsin K in diseases involving cartilage degradation. osteocalcin.53 Local increases in IGF1 concentration would stimulate osteoblastic differentiation. and skull deformities with delayed suture closure and open fontanels. and could augment bone formation. Bühling et al. was first described in 1962 by Marouteaux and Lamy. which are present in osteopetrotic diseases. parental consanguinity. The extent of solubilization seen with cathepsin K is comparable to that of bacterial collagen­ ase.26. the bone phenotype in the cathepsin‑K-knockout mouse is more weakly expressed than in humans with pycno­ dysostosis.42 found parental consanguinity in about 30% of reported cases.47. and the finding that this protease is expressed in bronchial epi­ thelial cells in humans. derived from the Greek pycnos (dense). The unique collagenolytic activity of cathepsin K. cathepsin K has been shown to degrade type II collagen. proptosis. c athepsin‑K-knockout mice have reduced body fat ­ content compared with wild type littermates. and nearly 100% by 96 h. and may be involved in the pathogenesis of pulmonary fibrosis.39 The charac­ teristic facial appearance includes calvarial bossing. Interestingly. some cathepsin‑K-knockout mice have increased osteoclast numbers. osteopontin.48 In contrast to initial reports.57 How­ e ver.28.51 Interestingly. Cathepsin K has been shown to efficiently degrade osteonectin but not fibronectin. In addition to the skeletal phenotype. is being studied. samples from patients with VOLUME 7  |  AUGUST 2011  |  449 © 2011 Macmillan Publishers Limited. and probable large fontanels that may have driven him to wear a hat much of the time.35.47. bones that are formed by intramembranous ossification.58 Thus. 33–37 Pycnodysostosis.22 The remaining 10% of the organic bone matrix consists of noncollagenous proteins. such as the calvariae and clavicles. are usually absent. Cathepsin‑K-knockout mice developed a more pronounced pulmonary fibrosis than their wild-type litter­ mates. under conditions of high-fat feeding. dys (defective). studies have shown that. hypoplasia of the mandible with obtuse mandibular angle. Deletion of the Ctsk gene in atherosclerosis-prone mice leads to decreased atherosclerotic plaque size and progression and induces plaque fibrosis.

50 One might perceive a theoretical therapeutic advantage by this rather small effect on bone formation: 450  |  AUGUST 2011  |  VOLUME 7 Pharmacokinetics Cathepsin K inhibitors are small molecules with good oral absorption.70 The bioavailability of relacatib was reported as 89% in rats and 28% in monkeys.66 In vitro. it is the concentration of these drugs in the resorption lacunae. ovariectomized monkeys treated with this drug demonstrated a decrease in the levels of bone resorption markers CTX and NTX compared with ovariectomized monkeys treated with vehicle. when challenged with bleo­ mycin.63 Monkey and human cathepsin K. they neither bind specifi­ cally to bone. cortical volume and trabecular volume. a more selective cathepsin K inhibitor. ovariectomized rabbits treated with two different cathepsin K inhibitors. dogs and monkeys. respectively. also demonstrated prevention of bone loss when compared with vehicle-treated animals. potently inhibits bone resorption in vitro and in vivo. in contrast to bisphos­phonates.nature.13 have provided the rationale for testing these drugs in the setting of tumor-induced bone loss. odanacatib is not significantly retained by bone tissue. 64 Preclinical studies have assessed the anti­ resorptive effect of cathepsin K inhibitors in the treatment of osteoporosis and tumor-induced bone loss. such as metabolic stability. making them susceptible to pharmaco­ kinetic interactions with other drugs. and V. the bioavailability of alendronate was 0. and. mice overexpressing cathepsin K have a lower degree of pulmonary fibrosis than wild-type mice. an inhibitor of human cathepsins K. There is a direct relationship between serum concentration and the concentration in bone. relatively unimpeded. treatment with cathepsin K inhibitors resulted in little to no reduction in bone formation rate—an observation that is unusual for an antiresorptive molecule. suggesting that cathepsin K over­ expression represents a protective mecha­nism to counteract the excessive matrix deposition in the develop­ ment of the disease. respectively. Unlike alendronate. 1. most cathepsin K inhibitors have been designed to show an optimal combination of potency and pharmacokinetic behavior. All rights reserved .63. while bone resorption is impaired. The observation that osteoclasts have a pivotal role in the formation of osteolytic lesions that accompany bone metastases.61 if bone formation is allowed to proceed.78 Despite optimized metabolic stability. In humans. making the use of non­ human primate models more appropriate than lower animal forms for studying these inhibitors in vivo .70 www.78 In addition.12. preclinical data in various animal models suggest that the oral bioavailability of cathepsin K inhibitors is formulation-dependent.8% and 1.73 Cathepsin K inhibitors show pharmacokinetics that are substantially different from other bone resorption inhibitors. cathepsin K inhibition reduced skeletal tumor burden by 62% when compared with vehicle.65–68 Relacatib.50.58.74. In accord with these data. one might expect more salutary effects on bone density and other aspects of bone quality. The lack of a major effect on bone formation suggests an uncoupling between bone resorption and bone formation under the influence of the cathepsin K inhibitors.79 Given their mechanisms of action.69 In a recent study. rats and dogs. Odanacatib prevented bone loss in ovariectomized monkeys without affecting bone formation rate. Cathepsin K inhibitors have been designed against the human enzyme to reversibly inhibit the activated form of the molecule. however.66 Similarly. and the fact that cathepsin K was found to be expressed in bone-residing tumor cells. pharmacokinetic studies in humans have been shown to be linear at the lower dose ranges but nonlinear at higher doses. L.9%. No effect on the growth of the tumor itself was observed. A recent study 67 demonstrated that mice treated with a cathepsin K inhibitor had fewer osteolytic lesions induced by breast tumors in bones. ovariecto­ mized monkeys treated for 9 months with relacatib showed decreased bone turnover markers and preserved areal bone mineral density (BMD) at the lumbar spine and femur when compared with vehicle-treated. when dosed as a suspension in 0. the oral bioavailability of alendronate is approximately 0. such as bisphosphonates and denosumab. Cathepsin K inhibitors in preclinical studies The development of cathepsin K inhibitors as a potential therapy for osteoporosis and other diseases associated with a relative dominance of bone resorption is note­worthy. Also. The use of cathepsin K inhibitors has also been evaluated in animal models of skeletal metastases. In vivo.58 Additional preclinical studies have evaluated the skeletal effects of odanacatib. are identical. these drugs are metabolized by enzymes such as the cytochrome CYP3A4. Although human data are currently not available.62 These inhibitors are less potent against mouse or rat cathepsin K. Intact and ovariectomized monkeys given odanacatib also showed gains in BMD and increased peak load. 43% and 100% in monkeys.75 In contrast to bisphosphonates. among other bone diseases.71.REVIEWS pulmonary fibrosis were also analyzed in this  © 2011 Macmillan Publishers Limited. Using non-aqueous vehicles. Moreover. when breast tumor cells were injected intravenously and metastasized to bone. human osteoclasts treated with relacatib showed a dose-related decrease in bone resorption. and higher than the oral bioavailability of bisphosphonates.71 By contrast. that is most relevant to their activity. Ovariectomized monkeys treated with odanacatib showed increased cortical thickness. the oral bioavailability of odanacatib was 18%.5% aqueous methyl cellulose.76 Similar to other small molecules. odanacatib and L‑235. nor are they sequestered into bone.77.7%. rather than the concentration at the bone surface. bioavailability was only 8% in rats and 6% in dogs. ovariectomized animals. Histomorphometry indicated that relacatib reduced indices of bone resorption at cancellous and cortical sites. cathepsin K inhibitors do not need to bind to bone in order to exert their action. 72 which is similar to that of other bisphosphonates. and it was found that mRNA levels of cathepsin K were threefold higher in patients with pulmo­nary fibrosis than in normal individuals.7% in rats.

placebo and active controlled parallel-group study enrolled 285 postmenopausal women aged 55–75 years old with a diagnosis of either osteoporosis by T‑score without fragility fractures. quantitative CT of the L1–L2 lumbar spine and proximal femur was performed at baseline and after 1 year of treatment.63 Balicatib Balicatib (AAE‑581) is a nitrile-based compound investigated by Novartis. leading to effective suppression of biochemical markers of bone resorption. alendronate 70 mg weekly. The most frequently reported adverse events in the ONO‑5334 groups were hypertension and dyspepsia.85 Relacatib Relacatib (SB‑462795) is an oral compound studied by GlaxoSmithKline. directly related to their serum concentrations. mainly reported as pruritus. After 12 months. in patients taking the study medication (particularly the 50 mg dose) compared with the placebo group.83 Two phase II trials (in osteoarthritis and osteopenia/osteoporosis). and MIV‑701/710. a non-basic and nonlysosomotropic nitrile-based molecule. L. including AFG‑495.79. Participants were assigned to receive placebo or one of four daily oral doses of balicatib (5.80 The pharmaco­ kinetics of these drugs. which was similar to the increase observed in patients treated with alendronate 70 mg (5. is currently ­ VOLUME 7  |  AUGUST 2011  |  451 © 2011 Macmillan Publishers Limited.2%). double-blind. with the greatest gain at the lumbar spine (5. but only the 50 mg and 300 mg doses showed improvements in trabecular and cortical bone at the hip. The study drug suppressed serum and urinary CTX and uNTX levels. Odanacatib Odanacatib (MK‑0822). or one of three regimens of oral ONO‑5334 (50 mg twice daily.86 Overall. and atorvastatin. ibuprofen. double-blind. all doses of ONO‑5334 were associated with significant BMD increases at the lumbar spine and total hip (integral region analyses).71 that non-selectively acts on cathepsins K.REVIEWS These points all lead to a summary one: namely that the onset and resolution of the antiresorptive effect of cathep­ sin K inhibitors are rapid and. a Medivir compound. achieving the greatest suppression throughout with the 300 mg dose. randomized. It is a monobasic. improvements in trabec­ ular and cortical bone BMD at the lumbar spine were seen with all three doses. several pharmaceutical companies are actively conducting clinical trials to this end. including a morphea-like syndrome. presenting properties of lysosomo­ tropism.81 Although the oral daily dose was generally well tolerated.79–81 medications that are commonly prescribed to patients with osteoporosis and osteoarthritis led to the decision to halt the further development of this compound. In addition. designed as multicenter.1%) achieved with the 300 mg dose. compared with 7% of those in the placebo and alendronate groups. Treatment for 12 months with balicatib 25 mg or 50 mg resulted in a dose-dependent decrease in bone resorption markers (serum CTX and urinary NTX [uNTX]) with no change in bone formation markers (bone-specific alkaline phosphatase [BSAP]. a marker of bone resorption. but not so selective in living cells. Although the increases in cortical BMD at the lumbar spine and total hip were similar to those in participants treated with alendronate. Participants were randomized to receive placebo.82 It is a highly selective inhibitor of cathepsin K in enzyme assays. L. N‑terminal propeptide of type I collagen [P1NP] and osteocalcin). balicatib was associated with a dose-related increase in BMD at the lumbar spine and total hip. and S expressed in skin fibroblasts. have been completed. or osteopenia by T‑score but with ≥1 vertebral fragility fracture. Thus.80 A multicenter. have not moved beyond phase I studies.80 In a subset of participants.63. No difference in the rate of dermal or subcutaneous adverse events was observed across all study groups. Dosedependent improvements in BMD were noted in the ONO‑5334 groups.84 These off-target dermatologic events might be explained by the lysosomo­ tropism of this basic compound.1% of all women treated with ONO‑5334. Femoral neck and total hip BMDs were similarly augmented in patients treated with the ONO‑5334 50 mg and 300 mg regimens.0. was suppressed in the alendronate group but was increased in the 100 mg ONO‑5334 group. potentially leading to inhibition of cathep­ sins B. it tends to accumulate in lysosomes and reaches inhibitory potency against other cathepsins that are present in these compartments. Nevertheless. An adverse profile with NATURE REVIEWS | RHEUMATOLOGY ONO‑5334 ONO‑5334 is a hydrazine-based cathepsin K inhibitor being developed by Ono Pharmaceutical. placebo-­ controlled studies. α‑heteroatom cyclic ketone63. the ONO‑5334 50 mg and 300 mg groups showed superior improvement of trabecular BMD at the femur. at least initially. and its phase II results have recently been published. 100 mg once daily or 300 mg once daily). Serious adverse events were reported in 11.63 Cathepsin K inhibitors in clinical trials Although no cathepsin K inhibitors have reached the stage where they have been reviewed or approved for clinical use. randomized. Despite the favorable skeletal end points. 25 or 50 mg). All rights reserved . 10. and V. This cathepsin K inhibitor was shown to have less impact on the suppression of bone formation markers: only the 300 mg regimen significantly decreased BSAP and P1NP levels. balicatib trials were discontinued due to dermatologic adverse effects. combined with their anti­ resorptive potencies. a nitrile-based Novartis compound.66 Clinical studies were discontinued after a phase I osteoporosis/osteoarthritis trial showed possible drug– drug interactions with paracetamol (acetaminophen). Calcium and vitamin D supplements were given to all patients.81 The osteopenia/­ osteoporosis study enrolled 675 postmenopausal women (mean age 62 years) with a mean T‑score at the lumbar spine <–2. allow for daily and more-convenient weekly dosing regimens. there were a greater number of skin reactions. tartrate-resistant acid phosphatase isoform 5b (TRAP5b). all doses of ONO‑5334 were well tolerated. Compared with placebo. Several agents.

CTX. The effect of three different classes of osteoclast inhibitors is shown with regard to their ability to reduce markers of bone resorption (red) or formation (blue).88 Women were re-randomized to receive either odanacatib 50 mg weekly or placebo. Image courtesy of Michael McClung (Portland. whereas the placebo. Odanacatib has a long half-life (66–93 h).3%). double-blind. with further gains seen at 24 months. placebo-controlled trial was designed as a 12-month study with a 12-month extension phase.7%). placebo-controlled extension study. The primary end point was the percentage change from baseline in lumbar spine BMD. but remained lower than in the placebo group at the end of the 24-month treatment period. with maximum suppression achieved early in the course of treatment with odanacatib (10. under development by Merck. Each phase I study tested various daily (n = 30) or weekly (n = 49) dosing regimens. Although BSAP and P1NP levels initially decreased with odanacatib treatment (10. This figure is not meant to represent a head-to-head comparison. 25 and 50 mg). in such a way that some participants received placebo for the entire 3 years (the PLB/PLB group).63. 3 mg and 10 mg groups showed a decline when compared to baseline levels. Participants were allocated to one of the weekly odanacatib treatment groups (3. An exception was noted in patients who received the lowest odanacatib dose (3 mg).REVIEWS Alendronate Decrease from baseline serum CTX and BSAP levels at 24 months (%) 0– –20 – –40 – –60 – –80 – –100 – Denosumab Odanacatib CTX BSAP Figure 2 | Effects of antiresorptive agents on bone remodeling. All rights reserved .9% at the lumbar www. patients on this regimen showed increased uNTX.77 Two randomized. 25 and 50 mg dosages). multicenter. Abbreviations: BSAP . further clinical trials tested weekly regimens of oral odanacatib. odanacatib did not interfere with bone formation to the same extent as other antiresorptive medications such as alendronate and denosumab.8% lower than controls) and 24 months (20. but there were no changes in TRAP5b levels or significant effects on BSAP or osteocalcin. Despite effectively suppressing bone resorption markers. The cathepsin K inhibitor odanocatib inhibits bone resorption markedly. receptor activator of nuclear factor κB. some were treated with odanacatib 50 mg for the entire 3 years (the ODN/ODN group). total hip and trochanter. bone-specific alkaline phosphatase. A dose-dependent suppression of bone resorption markers was noted for both the daily and weekly regimens. OR).5) at any of the following sites: lumbar spine. P1NP and BSAP levels. Distal 1/3 radius and total body BMD remained stable after 24 months in the 25 mg and 50 mg groups. However. The data for bone turnover markers are shown in Figure 3. Continuous odanacatib treatment for 3 years Of the 280 participants who completed the 24-month study described above.2% compared to baseline) and at 24 months (–51. femoral neck (+1. uNTX levels remained suppressed in the 50 mg group at 12 months (–60. A phase II randomized. 10. femoral neck. suppression of serum CTX levels was intermittent and tended to return towards baseline. 189 enrolled in a 1‑year doubleblind. Overall. RANKL. with changes in BMD at other sites and bone turnover 452  |  AUGUST 2011  |  VOLUME 7 markers as secondary end points.0 and ≥–3. After 24 months. C-terminal type I collagen telopeptide. The lowest dose studied (3 mg) differed markedly from the other doses.8% compared to baseline). It is highly selective for cathep­sin K. like the other two classes.6%). A dose-dependent increase in BMD at the lumbar spine and femoral sites was noted at 12 months in patients treated with odanacatib compared with the placebo group. they gradually increased after 6 months. serum CTX. with no reports of serious adverse effects. The cumulative gain in BMD after 3 years of treatment with odanacatib 50 mg was 7. in whom there were no significant increases in BMD at any site. leaving this process relatively unperturbed (Figure 2).87 This study enrolled postmenopausal women (n  = 399) with low BMD (T-score ≤–2. The women in the ODN/ODN group showed further improvement in BMD from year 2 to year 3 at the lumbar spine (+2. all doses were well tolerated and adverse events.2% lower than controls). as assessed by bone turnover markers. in which P1NP levels remained significantly lower than those in the control group at 12 months (31. and some received odanacatib 50 mg for 2 years followed by placebo for 1 year (the ODN/PLB group). Maximum suppression was observed at weekly doses ≥50 mg (CTX and uNTX both at 62% of baseline levels at day 21) and at daily doses ≥2.5 mg (CTX at 69% and uNTX at 79% of baseline levels at day 21). but has a small effect on bone formation. and trochanter (+2. with special attention to skin and pulmonary events. placebocontrolled phase I studies enrolled a total of 79 healthy postmenopausal women for a 3‑week course of odanacatib. with the exception of the 50 mg group. Note that the bisphosphonate (alendronate) and the anti-RANKL agent (denosumab) both reduce bone resorption and bone formation markedly. were similar in the treatment and placebo groups. which is independent of the dose or regimen.nature. 25 and 50 mg) or the placebo group. A dose-dependent increase in 1CTP levels was noted. ultimately showing no difference from those of controls. Dosedependent decreases in uNTX and serum CTX levels were also noted.87 The minimal off-target effects seen in the odanacatib clinical trials indicate the highly selective nature of odanacatib as a cathepsin K inhibitor. It was well  © 2011 Macmillan Publishers Limited.79 On the basis of these phase I results.600 IU weekly and a daily supplement of calcium 500 mg if dietary intake was less than 1 g per day. All participants received vitamin D3 5.

CTX. rather than NATURE REVIEWS | RHEUMATOLOGY affecting osteoclast survival per se. Bone Miner. By contrast. placebo. In contrast to NTX and CTX. This figure illustrates the rapid reversibility when ODN is discontinued. Abbreviations: BSAP. In contrast to other osteo­porosis treatment options.89 The maintenance of TRAP5b levels confirms the findings from preclinical studies that have shown either no change or an increase in osteoclast numbers. a decrease in markers of bone resorption generated by collagen cleavage (NTX and CTX) is observed. women who were previously treated with odanacatib 50 mg for 2 years showed significant bone loss.88 spine. NTX. other markers of bone resorption. P1NP . and the bone formation markers c | serum BSAP and d | serum P1NP. returning to baseline values by the end of the third year. but were not significantly different from the placebo group. Biochemical markers of bone resorption did not change significantly during the third year of odanacatib treatment. BSAP levels rose to 18% above baseline. J. VOLUME 7  |  AUGUST 2011  |  453 © 2011 Macmillan Publishers Limited.8% at the total hip. A. C-terminal type I collagen telopeptide. Discontinuation of odanacatib treatment In the ODN/PLB group. bone-specific alkaline phosphatase. Thereafter. were only transiently suppressed. PLB. 5. The cumulative decline in uNTX was 50% from baseline. compared to a 17% decline for those who received placebo for the 3‑year period. et al. Res. such as bisphosphonates. N‑terminal propeptide of type I collagen. TRAP5b levels also increased above baseline during 3 years of odanacatib treatment. The graphs show the geometric mean percentage change from baseline of the bone resorption markers a | urinary NTX and b | serum CTX. 1CTP levels were above baseline at 3 years and were higher than those in the placebo group. odanacatib 50 mg weekly for 2 years followed by placebo for 1 year (ODN/PLB) or placebo for 3 years (PLB/PLB). Reproduced with permission from Eisman. 242–251 (2011) © John Wiley and Sons.4% at the trochanter. J. TRAP5b is a marker of osteoclast survival.0% at the femoral neck.REVIEWS a Geometric mean percentage change from baseline 75 – 50 – 25 – 0– –25 – –50 – –75 – PLB/PLB ODN/PLB ODN/ODN b 150 – 125 – 100 – 75 – 25 – 0– –25 – –50 – –75 – –100 – c Geometric mean percentage change from baseline 40 – d 100 – 80 – 20 – 60 – 40 – 0– 20 – 0– –20 – –20 – –40 – –40 – 0 3 18 Time period (months) 27 36 –60 – 0 3 18 Time period (months) 27 36 Figure 3 | Graphic representation of the changes in bone markers in postmenopausal women treated with odanacatib 50 mg weekly for 3 years (ODN/ODN). All rights reserved . odanacatib. odanacatib perturbs osteoclast-mediated bone resorption by preventing cathepsin K degradation of collagen. ODN. such as serum CTX and urinary deoxypyridinoline. 5. Thus. and 7. reaching a nadir after approximately 6 months of treatment. The bone formation markers P1NP and BSAP fell initially. while P1NP levels returned to baseline by the end of year 3. N-terminal type I collagen telopeptide. which was most rapid during the first 6 months after discontinuation of active treatment. 26.

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The rapid reversi­bility observed upon discontinuation of odanacatib is similar to that seen with most other antiresorptive agents. BSAP and P1NP both increased during the first 6 months of year 3 (by 34% and 90%. D. H. Shi. Bone 28. Thomas. J. Quintanilla-Dieck. Rood. Invest.. 5. Exp. 18.. & Rodan. Y. L.. Raisz.. All papers identified were English-language. 57. Chapman. True. 8. Simon. & Libby. In addition. C. Ann. Sci. P . 3. 13.88 Three phase III trials of odanacatib in osteoporosis are currently ongoing to assess its safety. 90–98 (2009). Serum CTX levels also showed a similar rapid increase to 120% above baseline values. M. 165–172 (2006). Y. 195. R. Cathepsin K in adipocyte differentiation and its potential role in the pathogenesis of obesity. Cell Physiol. L. Xiao. Gene 446. J. J. R. vomiting and headache were the most common clinical 1. Genomic organization and chromosome localization of the human cathepsin K gene (CTSK). 89–96 (1995). Cathepsin K mRNA and protein expression in prostate cancer progression. W. E. respectively). all other adverse events were similar between the two groups. Treatment with odanacatib 5 mg daily for 4 weeks suppressed uNTX to the same extent as a single intravenous dose of zoledronic acid 4 mg (–77% [95% CI –82% to –71%] versus –73% [95% CI –80% to –62%]). Med. Drake.. Expression and regulation of cathepsin K in skin fibroblasts. but not cathepsins B. et al. 12. Brömme. “pycnodysostosis”. F. adverse events. 12511–12516 (1996). total hip and trochanter had returned to baseline levels. and “odanocatib”. Endocrinol.. Van Horn. the American Society of Bone and Mineral Research website was reviewed for relevant abstracts from past annual meetings (http://www. Brubaker. The regulation of cathepsin K gene expression. 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