Molecular Hydrogen and the Uremic Skeleton: A Critical Review and Turnover-State-Dependent Redox Hypothesis in CKD-MBD
Abstract
Chronic kidney disease-mineral and bone disorder (CKD-MBD) confers a substantial fracture burden that is only partly addressed by therapies targeting phosphate, parathyroid hormone, and vitamin D. Redox dysregulation may represent a complementary mechanism: reactive oxygen species (ROS) are required for receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclastogenesis, whereas excessive ROS impair Wnt/β-catenin signalling in osteoblast precursors and promote osteocyte dysfunction. Uremic toxins, inflammation, and dialysis further increase oxidative stress. Molecular hydrogen (H2) is a highly diffusible redox modulator that has been proposed to limit damaging radical-chain reactions while preserving physiological oxidant signalling. In non-uremic skeletal models, H2 consistently suppresses osteoclast differentiation and bone loss, but evidence for osteoblast rescue is heterogeneous. In CKD and dialysis, H2-based interventions have shown signals of reduced oxidative stress and symptomatic benefit; however, human evidence is predominantly observational, and no study identified in this review assessed a bone-specific endpoint. We therefore integrate uremic bone redox biology with H2 pharmacology and propose a turnover-state-dependent model in which H2 may restrain excessive resorption in high-turnover disease, while its net effect in low-turnover adynamic bone remains uncertain because potential osteoblast rescue competes with anti-osteoclastic activity…
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