Background
Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture [
1]. The disease is characterized by an imbalance in skeletal turnover such that bone resorption exceeds bone formation, thereby leading to a reduction in overall bone mass [
2]. Osteoporosis is usually diagnosed based on bone mineral density (BMD), and several biochemical markers are used to monitor bone resorption and bone formation. Drugs for osteoporosis are classified as antiresorptive drugs that inhibit bone resorption, such as bisphosphonates, and anabolic agents that stimulate bone formation, such as parathyroid hormone [
3]. Bisphosphonates are widely used first-line osteoporosis agents due to fracture prevention by BMD increase and prolonged antiresorptive effect after withdrawal [
4].
Cathepsin K, a member of the papain cysteine protease superfamily, is released by osteoclasts and degrades collagen of bone [
5]. Genetic evidence indicates a critical role of cathepsin K in bone resorption in humans and mice [
6‐
8]. Cathepsin K releases type I collagen crosslinks such as
N-telopeptides of type I collagen (NTX) and
C-telopeptides of type I collagen (CTX), which are widely used as diagnostic biomarkers for evaluation of osteoporosis [
9‐
11]. Therefore, several cathepsin K inhibitors have been examined as potential therapy for osteoporosis [
12‐
14]. ONO-5334 is an orally available cathepsin K inhibitor with established efficacy for increasing BMD and proven safety in a 2-year phase II study in osteoporosis (the OCEAN study) [
15‐
17]. In earlier phase I studies, ONO-5334 decreased serum CTX (sCTX) in a dose-dependent manner. Plasma ONO-5334 reached a maximum (Cmax) within 1.5 to 2 h of dosing and thereafter decreased in a biphasic manner, with a rapid initial phase followed by a slower phase. In repeated administration, the plasma ONO-5334 level just before the next dose (trough) reached steady state in 2 days after the first administration. Chemically, ONO-5334 is an α-amino acid derivative with a ketone, which differs from another cathepsin K inhibitor, odanacatib, an aliphatic nitrile [
18,
19]. These cathepsin K inhibitors have similar efficacy in clinical and non-clinical studies [
15,
16,
20‐
24], but the pharmacokinetic (PK) profiles were differ, with odanacatib developed as a once weekly treatment [
18,
25].
The OCEAN study was a randomized, double-blind, placebo- and active-controlled parallel-group trial performed to investigate the efficacy and safety of 100 mg once daily (QD), 300 mg QD and 50 mg twice daily (BID) ONO-5334 immediate release (IR) tablets [
16,
17]. ONO-5334 300 mg QD was chosen because phase I data suggested that ≥300 mg ONO-5334 showed a maximum suppressive effect on sCTX, and that 300 mg ONO-5334 maintained the suppressive effect on sCTX for 24 h after administration. ONO-5334 100 mg QD was added for evaluation of the dose response. ONO-5334 50 mg BID was chosen to compare the efficacy and safety of two regimens with a 100 mg total daily dose, to assess the potential for development of a slow release (SR) formulation. ONO-5334 increased BMD at all measured sites at 50 mg BID and 300 mg QD in the trial. A dose of 100 mg QD had less efficacy for increasing BMD compared to 50 mg BID and 300 mg QD. These findings suggest that a higher trough concentration of ONO-5334, rather than a higher Cmax, is more important for BMD increase. The drug was administered in the evening in the QD groups, and bone turnover markers were assessed only in the morning, based on bone resorption markers showing rhythmic variations and peaking at night [
26,
27]. Therefore, evaluation of the antiresorptive effect over 24 h and its relationship to BMD was limited in the OCEAN study. It was also difficult to calculate the antiresorptive effect over 24 h in phase I studies of ONO-5334 IR formulations because of limited sampling points for detection of significant changes in bone resorption markers.
In contrast, ONO-5334 SR formulations most likely maximize the potency of ONO-5334 by reducing Cmax and increasing exposure around the trough [
28]. In addition, the flat PK profile of ONO-5334 SR may minimize the lag-time between PK and pharmacodynamic (PD) inhibition of bone resorption markers. Therefore, ONO-5334 SR provided a better evaluation of the PK/PD relationship in our previous study [
29]. In an analysis excluding circadian variation of bone resorption markers, the plasma levels of bone resorption markers and ONO-5334 were fitted with sigmoidal maximal inhibitory effect (
Emax) models, simply reflecting inhibition of cathepsin K. Furthermore, Eastell et al. clearly showed that changes in sCTX inhibition with ONO-5334 SR morning vs. evening dosing parallel changes in the PK profile, highlighting a clear link between PK levels and antiresorptive effects [
30].
Even though the antiresorptive effect could only be monitored at one point in the morning in the OCEAN study, simulation can allow the antiresorptive effect to be assessed for 24 h and may provide a better assessment of the relationship of this effect with BMD increase. sCTX has the highest signal-to-noise ratio among serum and urinary NTX and CTX bone resorption markers [
29]. In this post-hoc analysis, the duration of antiresorptive effects, sCTX inhibition, and the relationship between antiresorptive effects and increases in BMD were investigated in postmenopausal patients with osteoporosis.
Discussion
Simulated sCTX inhibition quickly reached >99% Emax at 0.5 h at all doses, but then fell below 80% Emax at 100 mg QD and 50 mg BID, but not at 300 mg QD. The mean sCTX inhibition rates over 24 h at 100 mg QD, 300 mg QD and 50 mg BID were 63, 95 and 80% Emax, respectively. The longest sCTX inhibition occurred with 300 mg QD, followed in order by 50 mg BID and 100 mg QD. The observed increases in BMD at the lumbar spine and total hip in the OCEAN study showed strong relationships with mean sCTX inhibition over 24 h. Taken together, these data show that the mean antiresorptive effects of ONO-5334 over one day at 100 mg QD and 50 mg BID were <90% Emax. However, 300 mg QD gives almost maximal potential of 96% Emax for antiresorptive effect. These results show that simulation of antiresorptive effect over 24 h allows prediction of BMD increases due to ONO-5334.
All three clinical studies used in this post-hoc analysis included only postmenopausal Caucasian women. The mean age of the patients in the OCEAN study was slightly higher than in the MAD study, and the mean body weight in the OCEAN study was 7% lower than in the MAD study. Plasma ONO-5334 levels in the OCEAN study were comparable to those in the MAD study (Additional file
2). There were differences in baseline levels of bone resorption markers among studies, but these levels do not seem to influence the antiresorptive effect of cathepsin K inhibitors [
16,
25]. Consequently, the slight differences in baseline characteristics were considered not to be clinically relevant or to have significantly affected the outcome of the current analysis. Therefore, it was considered appropriate to estimate the antiresorptive effect of ONO-5334 in the OCEAN study based on data from the MAD and PKPD studies.
The timing of administration also differed among studies. ONO-5334 was administered in the morning in the MAD and PKPD studies, but the QD groups received ONO-5334 in the evening in the OCEAN study. PK is influenced by variation of physiological functions with time of day [
33,
34]. Among these factors, gastric pH may influence absorption of ONO-5334 because the solubility of ONO-5334 is high at acidic pH. Gastric pH transiently increases from pH 2 to pH 4 after a meal [
35], although PK parameters, Cmax and AUC of ONO-5334 do not differ significantly in postprandial administration compared with a fasted state [
18]. Dissolution of IR tablets is rapid (50% dissolution in vitro in <0.25 h). Therefore, the difference in timing of administration with ONO-5334 was unlikely to have significantly influenced the PK. However, the timing of administration may influence antiresorptive effects due to circadian rhythms in bone turnover, which reach a peak during the night/early morning and a nadir in the late afternoon [
26,
27]. Eastell et al. showed that changes in sCTX inhibition with ONO-5334 SR in morning vs. evening dosing parallel changes in PK [
30]. In addition, the sigmoidal
Emax model of sCTX with ONO-5334 SR was similar under fed and fasted conditions [
29]. Overall, these limitation in differences in PK are unlikely to have significantly influenced the simulation of levels of bone resorption markers.
This post-hoc analysis showed that the mean antiresorptive effect over 24 h had a significant positive relationship with observed increases in BMD in the OCEAN study. It is difficult to explain why the increase in BMD at 50 mg BID was higher than that at 100 mg QD from the observed sCTX and PK data in the OCEAN study, in which there was no marked difference in sCTX between the two groups at 12 months. However, the simulation of antiresorptive effect at 50 mg BID clearly showed higher sCTX inhibition compared with 100 mg QD, and thus may help to explain the change in BMD relative to changes in bone resorption. ONO-5334 SR can reduce excessive exposure and improve adherence by reducing dosing frequency from BID to QD. On the other hand, 300 mg QD was the most effective dose and regimen for a BMD increase in the OCEAN study, and had no safety concerns, even though Cmax was 74 times higher than that required for 99%
Emax [
16,
17]. In the current analysis, the antiresorptive effect over 24 h at 300 mg QD almost reached maximum inhibition. Several cathepsin K inhibitors have been reported [
18,
19,
36,
37] and these have different PK and safety profiles [
18,
25]. However, the maximal effects of drugs in the same class may not differ [
38] and the effect of 300 mg QD ONO-5334 may reflect the maximal effect of cathepsin K inhibitors on BMD. The maximal BMD increase with ONO-5334 was not less than that observed for odanacatib at 50 mg once weekly [
16,
23].
This study has a number of strengths, including use of a PK/PD analysis to evaluate specific regimens, dose response, and maximal response in the OCEAN study. However, there are also several limitations. First, this was a post-hoc analysis that used data that were not designed for the analysis. Second, there is a time mismatch between data at 2 weeks after repeated administration in the simulation and observed 1-year data in the OCEAN study. However, this mismatch was considered minimal because the antiresorptive effect and PK of ONO-5334 were stable and BMD gradually increased over 1 year [
16]. Third, the inhibitory effect on osteoblast function, e.g. P1NP, of cathepsin K inhibitors is slightly less than that of bisphosphonates [
16]. This is an important feature of cathepsin K inhibitors, but we used only antiresorptive effect to simplify the PK/PD analysis.
Acknowledgements
We thank all of our contributors for the work.