In the largest ever pediatric study to evaluate serum levels of RANKL (a transmembrane protein receptor activator of NF-κB ligand), osteoprotegerin (OPG), and RANKL:OPG ratio in healthy children, the data indicate significant differences in RANKL concentration and RANKL:OPG ratio by age, while OPG levels were not influenced by age, according to study results published in Bone.

Previous studies have shown RANKL is secreted by osteoblasts and binds to its receptor RANK, thus leading to osteoclast differentiation and activity. The bone resorption is further enhanced by the action of RANKL, as it also prevents osteoclast apoptosis. Conversely, OPG acts as a decoy receptor to bind RANKL and thereby blocks these effects.

The goal of the study was to quantify serum levels of RANKL and OPG, as well as the ratio between the two, in healthy children. Furthermore, the researchers assessed the influence of age, sex, body mass index (BMI), and other determinants on these levels.

The cross-sectional study was based on blood samples from children in a previous completed study and healthy children aged 1 to 21 years recruited from general pediatric clinics affiliated with Children’s Hospital Los Angeles. Patients were excluded if they had sustained a fracture in the past 6 months.

The study included 300 blood samples from the patients (173 boys, 58%; mean age, 11.64±4.84 years). The overall median RANKL concentration was 0.28 pmol/L (interquartile range [IQR], 0.19-0.38 pmol/L), median OPG concentration was 3.56 pmol/L (IQR, 2.92-4.25 pmol/L), and the median RANKL:OPG ratio was 0.08 pmol/L (IQR, 0.05-0.12 pmol/L).

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The children were divided into 4 groups based on age (<6 years, 6-10 years, 11-15 years, and 16-21 years). Levels of RANKL were lower with increasing age, other than in the 11 to 15 year age group, in which a slight increase was noted: 0.36 pmol/L, 0.28 pmol/L, 0.30 pmol/L, and 0.21 pmol/L, respectively (P =.0001). The trend was similar for RANKL:OPG ratio: 0.09, 0.08, 0.09, and 0.07, respectively (P =.0027), but not for OPG (P =.0646).

Categorization by BMI z score (<-2.0, -2.0 to 1.0, >1.0 to 2.0, and >2.0) indicated an inverse correlation with OPG, as there was a significant decrease in OPG levels with increased BMI z score: 5.27 pmol/L, 3.62 pmol/L, 3.39 pmol/L, and 3.01 pmol/L, respectively (P =.0123). In a similar fashion, RANKL concentrations were different between BMI z scores (P =.001).

RANKL levels were also significantly different between Tanner stages, with the highest RANKL levels seen at Tanner stage 3 (median concentration of 0.36 pmol/L) and the lowest levels with Tanner stage 5 (median concentration of 0.26 pmol/L; P =.048).

The researchers acknowledged several limitations of the study. First, they did not quantify total RANKL levels but only free soluble RANKL levels, with unknown clinical utility. Second, there is uncertainty as to whether the circulating levels of RANKL reflect levels in general or those in specific areas of interest. Third, no other bone markers were measured for comparison.

“This sizeable study of RANKL, OPG, and RANKL:OPG with parameters of physical development in healthy children is important to establish standards in these biochemical markers and to potentially create pediatric reference data,” concluded the investigators, adding that “[t]his may be a valuable clinical tool in evaluating children with specific disease subsets, in particular bone disorders where standard pediatric data is often unavailable.”

Disclosure: Multiple authors disclosed relationships with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

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Ali SA, Kang H, Olney R, et al. Quantifying RANKL and OPG levels in healthy children: a large cross-sectional analysis [published online June 14, 2019]. Bone. doi:10.1016/j.bone.2019.06.012