Hyperbaric oxygen therapy for osteoporosis: A systematic review of preclinical evidence and mechanisms

Hyperbaric oxygen therapy (HBOT) has been proposed as a direct anti-osteoporotic intervention rather than solely an adjunctive therapy. We systematically synthesized preclinical in vivo evidence and underlying mechanisms following PRISMA, with prospective registration (PROSPERO CRD42024525038), by searching PubMed, Embase, Cochrane Library, and Web of Science to November 2025. Of 3281 records, six studies (2016-2025) met inclusion across ovariectomy, hindlimb unloading, spinal cord transection, and D-galactose-induced aging models in Wistar and Sprague-Dawley rats. HBOT protocols most used 2.0-2.2 atm absolute with 85-100 % oxygen for 40-60 min per session. Across studies, HBOT improved bone mineral density and trabecular microarchitecture (e.g., BV/TV, Tb.Th, Tb.N), enhanced biomechanical strength, increased formation markers (e.g., procollagen type I N-terminal propeptide, bone-specific alkaline phosphatase, osteocalcin), and reduced resorption markers (e.g., C-terminal telopeptide of type I collagen, tartrate-resistant acid phosphatase-5b). Mechanistic signals converged on remodeling and vascular-metabolic pathways: modulation of the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) axis; restoration of Wnt/β-catenin signaling with reduced sclerostin; attenuation of oxidative and inflammatory stress (e.g., tumor necrosis factor-α); pro-angiogenic support (vascular endothelial growth factor, basic fibroblast growth factor); and neuropeptide-related effects (calcitonin gene-related peptide). Risk-of-bias profiles were mixed and heterogeneity precluded meta-analysis. Collectively, preclinical data indicate that HBOT mitigates osteoporotic bone loss primarily through coordinated, mechanisms of action that rebalance bone remodeling and improve the osteovascular milieu, while underscoring the need for standardized dosing parameters and rigorously designed human studies powered for clinically meaningful endpoints.