Effect of adrenocorticotropic hormone infusion on circulating sclerostin levels

Abstract

Glucocorticoid use is the most common cause of secondary osteoporosis. Poor skeletal health related to glucocorticoid use is thought to involve inhibition of the Wnt/β-catenin signaling pathway, a key pathway in osteoblastogenesis. Sclerostin, a peptide produced primarily by osteocytes, is an antagonist of the Wnt/β-catenin signaling pathway, raising the possibility that sclerostin is involved in glucocorticoids' adverse effects on bone. The aim of this study was to determine whether an acute infusion of cosyntropin (i.e. ACTH(1-24)), which increases endogenous cortisol, increases serum sclerostin levels as compared to a placebo infusion. This study was performed using blood samples obtained from a previously published, double-blind, placebo-controlled, randomized, cross-over study among healthy men and women who received infusions of placebo or cosyntropin after being supine and fasted overnight (ClinicalTrials.gov NCT02339506). A total of 17 participants were analyzed. There was a strong correlation (R2 = 0.65, P < 0.0001) between the two baseline sclerostin measurements measured at the start of each visit, and men had a significantly higher average baseline sclerostin compared to women. As anticipated, cosyntropin significantly increased serum cortisol levels, whereas cortisol levels fell during placebo infusion, consistent with the diurnal variation in cortisol. There was no significant effect of cosyntropin as compared to placebo infusions on serum sclerostin over 6-24 h (P = 0.10). In conclusion, this randomized, placebo-controlled study was unable to detect a significant effect of a cosyntropin infusion on serum sclerostin levels in healthy men and women.

Keywords: ACTH; bone; cortisol; glucocorticoid; sclerostin.

Figures

Figure 1

Inpatient study design. Participants completed two study visits in random order with a 1–3 months wash-out period between the visits. At one study visit, they received two 2.5 h infusions of placebo (0.9% saline) and at the other visit they received two 2.5 h infusions of synthetic ACTH(1–24) (cosyntropin) 70 µg/h. Scl refers to the assessment of sclerostin levels. These were taken at baseline (before the morning infusion), immediately preceding the end of the second infusion, and the following day (24 h after baseline measures). Sclerostin levels were evaluated for both arms of the study and at both visits for each participant. Study design diagram is adapted from our previously published study (Leung et al. 2020).

Figure 2

Baseline sclerostin correlated by visit. Bivariate correlation between each individual’s baseline sclerostin values at the placebo visit and cosyntropin visit. Baseline sclerostin measurements were significantly correlated, P < 0.0001 (linear regression). There was a wide range of baseline sclerostin levels, however, for a given individual it remained consistent over the 1–3 months wash-out period. Open circles denote female participants and solid triangles denote male participants.

Figure 3

Effect of ACTH and placebo infusion on sclerostin concentrations. Serum sclerostin measurements were taken at baseline (pre-infusion), at the end of the afternoon infusion (approximately 6.5 h after the start of the morning infusion), and the following day (24 h after baseline measures). Placebo visit is represented by the white boxes and ACTH visit by the gray boxes. Whiskers extend to maximum and minimum value, the box represents the interquartile range, X denotes the mean, and the line inside the box shows the median. Data points outside the whiskers show the outliers. A mixed model analysis showed no effect of cosyntropin vs placebo over time (P = 0.10).

Figure 4

Sclerostin 24-h change from baseline in females (n  = 7) and males (n  = 10) after placebo or ACTH infusion. Twenty-four-hour change from baseline in serum sclerostin for the placebo visit is represented by the white boxes and ACTH visit by the gray boxes. Females are shown on the left and males on the right. Whiskers extend to maximum and minimum value, the box represents the interquartile range, X denotes the mean, and the line inside the box shows the median. Data points outside the whiskers show the outliers. P values were obtained using a Fisher’s exact test for men and women separately.