Osteoprotegerin and receptor activator of NF-kappaB ligand as biomarkers for bone resorption-related disorders

Abstract

Osteoclastic bone diseases represent a significant health burden, especially in an aging population, due to imbalances in bone homeostasis that result in postmenopausal osteoporosis, inflammatory arthritis, malignancy-induced bone disease and secondary metabolic conditions, which result in fragility fractures, disability and death. Although advances in imaging and pharmacology have enhanced management, existing diagnostic strategies have poor sensitivity in detecting early-stage pathological changes or fracture risk. The NF-kappaB/receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin (OPG) pathway is important in bone turnover regulation, which is dysregulated in bone degradation, leading to increased osteoclast numbers and bone degradation. Circular levels of RANKL and OPG, particularly the RANKL/OPG ratio, have shown potential as biomarkers for early diagnosis, monitoring, and evaluating therapeutic response, with the RANKL/OPG ratio reflecting the balance of osteoclastogenic activity in the bone microenvironment and correlating with bone mineral density, fracture risk, and bone pathology. It exhibits lower biological variability and enhanced sensitivity for early disease detection compared with individual markers. This review assesses the experimental, translational and clinical evidence for the predictive and monitoring potential of RANKL and OPG, and correlations between various imaging techniques and circulating biomarkers to gain insight into disease progression. We explore and discuss the limitations with regards to methodological issues, assay variability and biological variability, and the therapeutic implications of modulating the RANKL/OPG axis, highlighting its potential in informing treatment approaches and improving outcomes in bone resorptive diseases.

Keywords: Receptor activator of NF-kappaB; Receptor activator of NF-kappaB/receptor activator of NF-kappaB ligand; Osteoprotegerin axis; Osteoclast; Osteoporosis

Core Tip: The receptor activator of NF-kappaB/receptor activator of NF-kappaB ligand (RANKL)/osteoprotegerin (OPG) pathway is a pivotal bone remodeling pathway, and its disruption is responsible for osteoclast-driven bone resorption in osteoporosis, arthritis and bone-related cancer. Plasma RANKL and OPG, and their ratio, may be more sensitive indicators for diagnosis, fracture prediction and therapy assessment. While assays are variable, there is evidence that the RANKL/OPG ratio could be a better predictor than either marker alone, with potential to improve diagnosis, treatment and outcomes in bone resorption disease.