Changes in RANKL, OPG, and 25(OH)D Levels in Children with Leukemia from Diagnosis to Remission

Abstract

Background: The receptor activator of the nuclear factor-kB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway is a determining pathway in the balance between bone formation and resorption, and disruptions in this complex can affect bone metabolism.

Methods: This study analyzes the changes in RANKL, OPG, and 25(OH)D levels; the RANKL/OPG ratio; and other bone turnover markers (BTMs) from diagnosis to complete remission in children with acute lymphoblastic leukemia (ALL). This is a prospective observational cohort study, carried out at the Instituto Mexicano del Seguro Social, Mexico City, including 33 patients (4-17 years) with newly diagnosed B-cell ALL. The patients were treated with the HP09 chemotherapy protocol. Children who had previously been treated with corticosteroids were excluded. A peripheral blood sample at diagnosis and remission was collected to determine the 25(OH)D and BTM concentrations.

Results: Increased RANKL (p = 0.001) and osteocalcin (p < 0.001) levels and RANKL/OPG ratio (<0.001) and a decreased OPG level (p = 0.005) were observed at remission, predominantly in the high-risk (HR) relapse and vitamin D deficiency groups. A negative association between RANKL and OPG (r = -0.454, p = 0.008) was observed.

Conclusions: we suggest that the RANKL/OPG ratio could serve as a bone remodeling marker in ALL patients.

Keywords: 25(OH)D; RANK ligand; acute lymphoblastic leukemia; bone turnover markers; corticosteroids; osteoprotegerin.

Figure 1

Study flow-chart in patients with ALL.

Figure 2

Changes in 25(OH)D, BMT, and RANKL/OPG ratio between diagnosis (baseline) and remission time in patients with ALL. Significant differences between the two time points were determined by Wilcoxon signed rank test. (A) 25(OH)D; (B) RANKL, receptor activator for nuclear factor kB ligand; (C) OPG, osteoprotegerin; (D) RANKL/OPG ratio; (E) osteocalcin; (F) BAP, bone alkaline phosphatase; (G) TRACP-5b, tartrate-resistant acid phosphatase. BAP and TRACP-5b, sample size analyzed n = 20. Sufficiency 25(OH)D ≥ 30 ng/mL (dotted green), and deficiency 25(OH)D < 20 ng/mL (dotted red).

Figure 3

Changes in 25(OH)D3, bone turnover markers, and RANKL/OPG ratio between diagnosis (baseline) and remission time by risk of relapse in patients with ALL. Significant differences between the two time points were determined by Wilcoxon signed rank test. (A) 25(OH)D; (B) RANKL, receptor activator for nuclear factor kB ligand; (C) OPG, osteoprotegerin; (D) RANKL/OPG ratio; (E) osteocalcin; (F) BAP, bone alkaline phosphatase; (G) TRACP-5b, tartrate-resistant acid phosphatase. Standard or intermediate risk of relapse (n = 12) and high risk of relapse (n = 21). BAP and TRACP-5b sample size analyzed n = 20. Sufficiency 25(OH)D ≥ 30 ng/mL (dotted green), and deficiency 25(OH)D < 20 ng/mL (dotted red).

Figure 4

Changes in bone turnover markers and RANKL/OPG ratio between diagnosis (baseline) and remission time according to vitamin D status in patients with ALL. Significant differences between the two time points were determined by Wilcoxon signed rank test. (A) RANKL, receptor activator for nuclear factor kB ligand; (B) OPG, osteoprotegerin; (C) RANKL/OPG ratio; (D) osteocalcin. Insufficient vitamin D (n = 10) levels, deficient vitamin D levels (n = 20).

Figure 5

Spearman’s correlations between (A) vitamin D concentrations and cumulative corticosteroid doses and (B) OPG and RANKL in patients with ALL at remission time.