ONO-5334, a cathepsin K inhibitor, improves bone strength by preferentially increasing cortical bone mass in ovariectomized rats

Ochi, Yasuo; Yamada, Hiroyuki; Mori, Hiroshi; Kawada, Naoki; Kayasuga, Ryoji; Nakanishi, Yasutomo; Tanaka, Makoto; Imagawa, Akira; Ohmoto, Kazuyuki; Kawabata, Kazuhito

doi:10.1007/s00774-013-0542-x

Cited by 14 publications

(6 citation statements)

References 26 publications

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“…We think the reason why there was no significant difference was that the sample size was small and the analysis period was short. ONO-5334 has shown potent selective inhibition of cathepsin K in vitro and has resulted in improvement in both BMD and bone strength in osteoporosis models ( Ochi et al, 2014 ; Eastell et al, 2014 ; Engelke et al, 2014 ; Yamada et al, 2016 ). In the first clinical study of ONO-5334, Eastell et al (2011) investigated the efficacy and safety of the compound in postmenopausal women with osteoporosis.…”

Section: Discussionmentioning

confidence: 99%

“…A CKI (ONO-KK1-300-01; Ono Pharmaceutical, Osaka, Japan) was dissolved in 0.5% methyl cellulose (catalog 155496; Wako Pure Chemical Industries, Osaka, Japan) and administered orally at a dose of 15 mg/kg daily, thus initiating sensitization, until death at 4 weeks. The dose used was based on a previous observation and is considered to be appropriate in experimental animals ( Ochi et al, 2014 ). We selected this dose in order to investigate the effect of this CKI on arthritis during a 4-week observational period.…”

Section: Methodsmentioning

confidence: 99%

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Effect of a cathepsin K inhibitor on arthritis and bone mineral density in ovariectomized rats with collagen-induced arthritis

et al. 2018

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ObjectivesCathepsin K is expressed by osteoclasts and synovial fibroblasts and degrades key components of bone and cartilage. Inhibition of cathepsin K protease activity may be beneficial for the prevention of bone erosion and cartilage degradation in rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) rat model is well established for studying the pathology and treatment of RA. We investigated the effect of ONO-KK1-300-01, a cathepsin K inhibitor (CKI), on arthritis and bone mineral density (BMD) in rats with CIA.MethodsSeven-month-old female Sprague Dawley rats were divided into 5 groups: rats without CIA (CNT); CIA rats that underwent ovariectomy (OVX) and were treated with CKI; CIA rats that underwent OVX and were treated with vehicle (Veh); CIA rats that underwent sham surgery and were treated with CKI; and CIA rats that underwent sham surgery and were treated with Veh. CKI was orally administered at a dose of 15 mg/kg, thus initiating collagen sensitization, until death at 4 weeks. We evaluated hind paw thickness and the arthritis score every week until death. Radiographs of the resected left foot were obtained with a soft X-ray apparatus. Destruction of bone and cartilage was classified and scored as previously described by Engelhardt et al. BMD was measured by bone densitometry at the halfway point between the distal metaphysis and the diaphysis of the resected right femur. We also performed histomorphometry of the proximal left tibia, histological evaluation of arthritis, and a bone strength test.ResultsCKI administration significantly reduced hind paw thickness and the arthritis score, and prevented a decrease in BMD. The radiographic score was significantly lower in the CKI group than in the Veh group. In the histomorphometric analysis, bone-resorption parameters were significantly lower in the CKI groups than in the Veh groups. CKI significantly inhibited synovial proliferation in the CIA rats. In the bone strength test, the ultimate stress was significantly higher in the CKI groups than in the Veh groups.ConclusionOur findings indicate that cathepsin K inhibitors may inhibit systemic and local bone loss, ameliorate arthritis, and attenuate the decrease of bone strength in an animal model of arthritis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Effect of a cathepsin K inhibitor on arthritis and bone mineral density in ovariectomized rats with collagen-induced arthritis

et al. 2018

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“…Currently, there are a variety of CTSK inhibitors reported in the previous literature ( Table 2 ), and some of them have been studied in preclinical studies, such as relacatib (SB-462795) [ 149 ], L-235 [ 150 ], balicatib (AAE-581) [ 151 ], odanacatib [ 152 ] and ONO-5334 [ 153 ]. They are taken orally and are able to significantly reduce the biochemical markers of bone resorption, serum CTX and urinary NTX levels and increase the bone mineral density.…”

Section: Ctsk Is a Potential Therapeutic Target For Cancersmentioning

confidence: 99%

Cathepsin K: A Versatile Potential Biomarker and Therapeutic Target for Various Cancers

Qian

Zhang

et al. 2022

Current Oncology

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Cancer, a common malignant disease, is one of the predominant causes of diseases that lead to death. Additionally, cancer is often detected in advanced stages and cannot be radically cured. Consequently, there is an urgent need for reliable and easily detectable markers to identify and monitor cancer onset and progression as early as possible. Our aim was to systematically review the relevant roles of cathepsin K (CTSK) in various possible cancers in existing studies. CTSK, a well-known key enzyme in the bone resorption process and most studied for its roles in the effective degradation of the bone extracellular matrix, is expressed in various organs. Nowadays, CTSK has been involved in various cancers such as prostate cancer, breast cancer, bone cancer, renal carcinoma, lung cancer and other cancers. In addition, CTSK can promote tumor cells proliferation, invasion and migration, and its mechanism may be related to RANK/RANKL, TGF-β, mTOR and the Wnt/β-catenin signaling pathway. Clinically, some progress has been made with the use of cathepsin K inhibitors in the treatment of certain cancers. This paper reviewed our current understanding of the possible roles of CTSK in various cancers and discussed its potential as a biomarker and/or novel molecular target for various cancers.

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“…Cathepsin K inhibitors including odanacatib [ 4 ] and ONO-5334 are a new class of drugs against osteoporosis which are undergoing clinical development. ONO-5334 improved bone strength by preferentially increasing cortical bone mass in ovariectomized rats [ 5 ] and significantly improved cortical and trabecular bone mineral density (BMD) in postmenopausal women with osteoporosis following 24 months of therapy [ 6 ]. In healthy postmenopausal women, ONO-5334 100 mg sustained-release tablet (SRT) administered in the morning exhibited a median time to maximum plasma concentration ( T max ) of 4 h and mean half-life of 15 h following repeat administration [ 7 , 8 ], suggesting the feasibility of once-daily dosing.…”

Section: Introductionmentioning

confidence: 99%

Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial

et al. 2015

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SummaryThe cathepsin K inhibitor, ONO-5334, improves bone mineral density in postmenopausal women with osteoporosis. The effects of morning versus evening administration of ONO-5334 were investigated by measuring bone turnover marker levels in healthy postmenopausal women. Morning administration of ONO-5334 showed a more consistent suppressive effect on bone resorption than evening administration.IntroductionBone turnover is thought to be subject to circadian variation, and the efficacy of osteoporosis treatments may be optimized by regulating the time of dosing. This study assessed whether evening administration of the cathepsin K inhibitor, ONO-5334, had a differential effect on the bone turnover marker, C-terminal telopeptide of type I collagen (CTX-I), compared with morning administration.MethodsThis was a single-center, single blind crossover study. Fourteen healthy postmenopausal women were assigned to receive ONO-5334 150 mg once daily for 5 days in each period; they were randomized to receive either evening doses in the first period and morning doses in the second or vice versa. Serum and urinary levels of CTX-I were measured throughout the study.ResultsBoth regimens showed similar patterns of reduction in serum and urinary CTX-I; however, CTX-I suppression was more consistently >60% over 24 h following morning administration. Morning administration led to 6% greater suppression of 24-h serum CTX-I area under the effect curve (AUE; 69 vs 63%; P < .05) and 7% greater suppression of urinary CTX-I/creatinine AUE (93 vs 86%; P < .01) than evening administration. Higher plasma ONO-5334 concentrations were observed between 12 and 24 h postdose following morning administration, with mean trough concentrations for the morning and evening regimens at 9.4 and 4.0 ng/mL, respectively. There were no safety findings of concern.ConclusionMorning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing.Trial registrationClinicalTrials.gov: NCT01384188, registered on June 27, 2011EudraCT: 2008-006284-37Electronic supplementary materialThe online version of this article (doi:10.1007/s00198-015-3342-4) contains supplementary material, which is available to authorized users.

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ONO-5334, a cathepsin K inhibitor, improves bone strength by preferentially increasing cortical bone mass in ovariectomized rats

Cited by 14 publications

References 26 publications

Effect of a cathepsin K inhibitor on arthritis and bone mineral density in ovariectomized rats with collagen-induced arthritis

Effect of a cathepsin K inhibitor on arthritis and bone mineral density in ovariectomized rats with collagen-induced arthritis

Cathepsin K: A Versatile Potential Biomarker and Therapeutic Target for Various Cancers

Morning vs evening dosing of the cathepsin K inhibitor ONO-5334: effects on bone resorption in postmenopausal women in a randomized, phase 1 trial

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