Effects of 16-month treatment with the cathepsin K inhibitor ONO-5334 on bone markers, mineral density, strength and histomorphometry in ovariectomized cynomolgus monkeys

Yamada, Hiroyuki; Ochi, Yasuo; Mori, Hiroshi; Nishikawa, Satoshi; Hashimoto, Yoshiaki; Nakanishi, Yasutomo; Tanaka, Makoto; Bruce, Mark; Deacon, Steve; Kawabata, Kazuhito

doi:10.1016/j.bone.2016.02.014

Cited by 10 publications

(9 citation statements)

References 35 publications

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“…The three-dimensional (3D) images were rebuilt by the software (CTVol, Skyscan). There were 50 consecutive slices (1.5 mm) selected as the region of interest beginning 6.22 mm away from the distal femur growth plate to analyze the trabecular bone (Yamada et al, 2016). For the quantitative analysis, the following measurements were obtained by the software: bone volume/tissue volume (BV/TV), bone surface/bone volume (BS/BV), trabecular thickness (Tb.Th), trabecular number (Tb.N), mean trabecular spacing (Tb.Sp), and bone mineral density (BMD).…”

Section: Methodsmentioning

confidence: 99%

Beneficial Effects and Toxicity Studies of Xian-ling-gu-bao on Bone Metabolism in Ovariectomized Rats

Zhong

Wang

et al. 2017

Front. Pharmacol.

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Xian-ling-gu-bao (XLGB) is a well-known patented traditional Chinese prescription widely used to treat osteoporosis, osteoarthritis, aseptic bone necrosis, or climacteric syndrome. However, recent reports have suggested that XLGB may cause liver injury in humans. In the present study, we aimed to evaluate the efficacy of XLGB in the prevention of osteoporosis in the zebrafish and ovariectomized (OVX) rats, both of which have been used as osteoporosis models. The safety of XLGB after long-term administration to OVX rats was also assessed. OVX rats were administered by oral gavage 270 mg/kg (recommended daily dose), 1350 mg/kg, and 1800 mg/kg of XLGB for 26 weeks. Bone mineral density, relative bone surface to bone volume, relative bone volume to total volume, trabecular number, mean trabecular thickness, and mean trabecular spacing in OVX rats were examined at the end of the 26-week dosing period. Additionally, OPG and RANKL expression in the femur were determined by western blot and immunohistochemical staining. To evaluate the safety of XLGB, body weight, hematology, serum biochemistry markers related to toxicology, and organ histopathology were determined in each group of OVX rats. Conversely, the zebrafish was treated with prednisolone to induce osteoporosis in the embryo. Disodium etidronate was used as a treatment control. XLGB was shown to be effective in preventing osteoporosis in both the OVX rats and the prednisolone-treated zebrafish. Similarly, XLGB increased OPG protein and decreased RANKL protein in OVX rats. Interestingly, no obvious toxicity was observed in the heart, liver, kidney, small intestine, or stomach at dosages of up to 1800 mg/kg after treating the OVX rats for 26 weeks. XLGB was shown to be very effective in treating osteoporosis in OVX rats. No obvious toxicity or adverse effects developed in OVX rats at dosages up to 1800 mg/kg, which is equivalent to six times the daily-recommended dose. Therefore, XLGB should be considered a good option for the treatment of post-menopausal osteoporosis.

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Section: Methodsmentioning

confidence: 99%

Beneficial Effects and Toxicity Studies of Xian-ling-gu-bao on Bone Metabolism in Ovariectomized Rats

Zhong

Wang

et al. 2017

Front. Pharmacol.

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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%

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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“…Animals received test articles for 9 weeks from the day of the first sensitization. The dose level of ONO-5334 was decided based on the results from an OVX monkey osteoporosis study [18]. ONO-5334 at 30 mg/kg prevented OVX-induced decreases in bone mass and strength.…”

Section: Methodsmentioning

confidence: 99%

“…ONO-5334 is a low molecular weight synthetic inhibitor of cathepsin K with Ki value of 0.1 nM [17]. In previous studies, we have shown that ONO-5334 suppresses bone resorption and increases bone mineral density in ovariectomized (OVX) cynomolgus monkeys [18, 19] and in patients with postmenopausal osteoporosis [20, 21]. The monkey CIA model may be more suitable for prediction of clinical efficacy in RA than rodent CIA models because monkeys are phylogenetically and physiologically close to human beings [22, 23].…”

Section: Introductionmentioning

confidence: 99%

Effects of the Cathepsin K Inhibitor ONO-5334 and Concomitant Use of ONO-5334 with Methotrexate on Collagen-Induced Arthritis in Cynomolgus Monkeys

Yamada

Mori

Nakanishi

et al. 2019

International Journal of Rheumatology

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We examined whether the cathepsin K inhibitor, ONO-5334, administered alone or in combination with methotrexate (MTX), could ameliorate joint destruction evoked by collagen-induced arthritis (CIA) in female cynomolgus monkeys. CIA was induced by immunizing with bovine type II collagen. ONO-5334 (30 mg/kg/day) was orally administered once daily and MTX (10 mg/body/day) twice weekly for 9 weeks. X-ray (evaluation of joint destruction) and swelling (inflammatory) scores of proximal interphalangeal (PIP), distal interphalangeal (DIP), and metacarpophalangeal (MP) joints were evaluated. Urinary concentrations of C-terminal telopeptide of type I collagen (CTX-I) and type II collagen (CTX-II) were measured. Arthritis, accompanied by bone and cartilage destruction, was successfully induced in this collagen-induced arthritis monkey model. ONO-5334 showed no suppressive effect on joint swelling, while the joint swelling scores in the MTX and combination (ONO-5334 + MTX) groups were less than 50% compared with the control group. ONO-5334 decreased X-ray score by a mean of 64% (p<0.05 vs the control group), and MTX also decreased in X-ray score by a mean of 46% but with no statistical significance. Combination of ONO-5334 and MTX further decreased the X-ray score by 28% over MTX group (74% reduction vs the control group, p<0.01). Maximum increase in CTX-I (10-fold) and CTX-II (7-fold) compared to baseline was observed at 7 and 3 weeks after the first sensitization, respectively. After treatment with ONO-5334 alone or in combination with MTX, concentrations were maintained near baseline for both markers. In conclusion, ONO-5334 prevented joint destruction but not joint inflammation in this monkey CIA model. Concomitant use of ONO-5334 with MTX reduced architectural joint destruction compared to MTX alone; therefore, ONO-5334 may help to prevent joint destruction in combination with MTX for the treatment of rheumatoid arthritis.

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Effects of 16-month treatment with the cathepsin K inhibitor ONO-5334 on bone markers, mineral density, strength and histomorphometry in ovariectomized cynomolgus monkeys

Cited by 10 publications

References 35 publications

Beneficial Effects and Toxicity Studies of Xian-ling-gu-bao on Bone Metabolism in Ovariectomized Rats

Beneficial Effects and Toxicity Studies of Xian-ling-gu-bao on Bone Metabolism in Ovariectomized Rats

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

Effects of the Cathepsin K Inhibitor ONO-5334 and Concomitant Use of ONO-5334 with Methotrexate on Collagen-Induced Arthritis in Cynomolgus Monkeys

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