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

ABSTRACT: The 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.Bone 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.This 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.Both 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.Morning dosing of ONO-5334 is more efficacious at reducing markers of bone turnover in healthy postmenopausal women than evening dosing.ClinicalTrials.gov: NCT01384188 , registered on June 27, 2011 EudraCT: 2008-006284-37.

SUBMITTER: Eastell R

PROVIDER: S-EPMC4715857 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Eastell R R Dijk D-J DJ Small M M Greenwood A A Sharpe J J Yamada H H Yuba M M Tanimoto M M Deacon S S

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 20151007 1

<h4>Unlabelled</h4>The 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.<h4>Introduction</h4>Bone turnover is thought to be subject to circadian variation, and ...[more]

PMID: 26446770

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Project description:Binge alcohol consumption elicits acute and robust increases of muscle sympathetic nerve activity (MSNA), yet the impact of evening binge drinking on morning-after MSNA is unknown. The present study examined the effects of evening binge alcohol consumption on polysomnographic sleep and morning-after MSNA. We hypothesized that evening binge drinking (i.e. 4-5 drink equivalent in <2 h) would reduce sleep quality and increase morning-after blood pressure (BP) and MSNA. Following a familiarization night within the sleep laboratory, 22 participants (12 men, 10 women; 25 ± 1 yr) were examined after simulated binge drinking or fluid control (randomized, crossover design). Morning MSNA was successfully recorded across both conditions in 16 participants (8 men, 8 women) during a 10-min baseline and three Valsalva's maneuvers (VM). Binge drinking reduced rapid eye movement (REM) sleep (15 ± 1 vs. 20 ± 1%, P = 0.003), increased stage II sleep (54 ± 1 vs. 51 ± 1%, P = 0.002), and increased total urine output (2.9 ± 0.2 vs. 2.1 ± 0.1 liters, P < 0.001) but did not alter morning-after urine specific gravity. Binge drinking increased morning-after heart rate [65 (54-72) vs. 58 (51-67) beats/min, P = 0.013] but not resting BP or MSNA. Binge drinking elicited greater sympathoexcitation during VM (38 ± 3 vs. 43 ± 3 bursts/min, P = 0.036). Binge drinking augmented heart rate (P = 0.002), systolic BP (P = 0.022), and diastolic BP (P = 0.037) reactivity to VM phase IV and blunted cardiovagal baroreflex sensitivity during VM phases II (P = 0.028) and IV (P = 0.043). In conclusion, evening binge alcohol consumption disrupted REM sleep and morning-after autonomic function. These findings provide new mechanistic insight into the potential role of binge drinking on cardiovascular risk.NEW & NOTEWORTHY Chronic binge alcohol consumption is associated with future cardiovascular disease (CVD) risk in both men and women. In addition, binge alcohol consumption is known to disrupt normal sleep quality during the early morning hours, coinciding with the morning sympathetic surge. In the present study, an evening of binge alcohol consumption increased baseline morning heart rate and cardiovascular reactivity during the Valsalva maneuver (VM) strain. Specifically, muscle sympathetic nerve activity and phase IV hemodynamic responses increased during VM the morning after binge alcohol consumption. The autonomic dysfunction and increased cardiovascular reactivity during VM suggests a contributing mechanism to CVD risk present in individuals who binge drink.

Dataset Information

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

Publications

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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