Metabolic checkpoints in bone remodeling: from dysregulation to targeted therapies

Abstract

Bone remodeling depends on a tightly regulated metabolic crosstalk between osteoblasts and osteoclasts. The article advances a hypothesis‑driven framework that positions discrete metabolic checkpoints ‒ glycolytic flux, mitochondrial Oxidative Phosphorylation (OXPHOS), amino‑acid utilization, and ion‑channel-coupled calcium signaling ‒ as tractable levers for restoring formation-resorption balance. The authors explicitly examine metabolic heterogeneity within and across osteolineages and disease contexts, integrate immune-metabolic coupling that links TCA‑cycle intermediates to RANKL/OPG regulation, and synthesize evidence on the efficacy and trade‑offs of current and emerging therapies (e.g., sclerostin/Wnt restoration, RANKL blockade, HIF‑1α modulation, and calcium‑channel targeting). To avoid over‑interpretation, clinical statements are constrained to the strength of available evidence; preclinical findings are labeled accordingly. The authors further propose a pragmatic framework for precision modulation ‒ rather than blanket inhibition ‒ of metabolic pathways to minimize off‑target toxicity and enable context‑dependent benefit. This consolidated view reframes metabolic dysfunction as a driver of skeletal pathology and a blueprint for targeted interventions.