Background/Purpose:
Bone turnover markers
(BTMs) respond faster than bone mineral density as an indicator of response to
therapy in osteoporotic patients; however, it remains unclear when and how best
to evaluate treatment response using BTMs. Denosumab (DMAb) has a dynamic BTM
profile over the 6-month dosing period (ie, reduction in turnover with release
of inhibition at the end of the dosing interval). This analysis assessed
the use of potential target values for serum C-telopeptide of type 1
collagen
(CTX) and serum procollagen type 1 N-terminal propeptide (P1NP) to explore
guidance to clinicians for monitoring postmenopausal
women with osteoporosis (PMO) during treatment.

Methods:
BTMs measured at
baseline in treatment-naïve PMO entering FREEDOM, a large randomized,
placebo-controlled study of DMAb (Cummings et al NEJM 2009), were used
to derive threshold values at the 5th percentiles of the observed distributions. The
relevant values for serum CTX (N = 7594) and P1NP (N = 1023) were 0.2 ng/mL and 25.8
ng/mL, respectively. These BTM target
values were applied to the study
populations of DECIDE (Brown et al JBMR 2009) and STAND (Kendler et al JBMR
2010) enabling evaluation of a population-based assessment of BTM target
values. DECIDE (N = 1189) and STAND (N = 504) were phase 3, randomized,
double-blind, double-dummy studies to compare the efficacy and safety of DMAb
(60 mg subcutaneously every 6 months) with alendronate (ALN; 70 mg weekly oral
tablet) in treatment-naïve PMO or PMO already receiving ALN, respectively. The
percentage of subjects in each treatment group with BTMs below the predefined target
values was evaluated
midcycle at month 3 after the 1st dose of DMAb, which also enabled trough values for ALN, and then re-evaluated
at month 9. Subjects with BTM values below the predefined targets at baseline were excluded from the analysis.

Results:
A
total of 1112 (93.5%) women in
DECIDE and 155 (30.8%) women in STAND had CTX values ≥ 0.2 ng/mL and
P1NP values ≥ 25.8 ng/mL at baseline. Table 1 reports the percentage of subjects with CTX
and P1NP values below the respective targets at months 3 and 9. The predefined
target values were almost universally achieved at 3 and 9 months on DMAb,
whereas the target for CTX, for example, on ALN was only achieved in 49.1% and
19.0% of treatment-naïve and ALN-pretreated PMO, respectively, at month 3.

Conclusion:
In this population-based analysis, in
both treatment-naïve and pretreated PMO, BTMs have utility in determining
response, and awareness of failure to reach a treatment target may help improve
clinical management.