Hyperbaric Oxygen Therapy for the Treatment of Bone-Related Diseases

Abstract

Hyperbaric oxygen therapy (HBOT) is a therapeutic modality that enhances tissue oxygenation by delivering 100% oxygen at pressures greater than 1 absolute atmosphere. In recent years, HBOT has shown considerable potential in the treatment of bone diseases. While excess oxygen was once thought to induce oxidative stress, recent studies indicate that when administered within safe limits, HBOT can notably promote bone healing and repair. Extensive basic research has demonstrated that HBOT can stimulate the proliferation and differentiation of osteoblasts and encourage bone angiogenesis. Furthermore, HBOT has been shown to exert a beneficial influence on bone metabolism by modulating the inflammatory response and redox status. These mechanisms are closely related to core issues of bone biology. Specifically, in the context of fracture healing, bone defect repair, and conditions such as osteoporosis, HBOT targets the key bone signaling pathways involved in bone health, thereby exerting a therapeutic effect. Several clinical studies have demonstrated the efficacy of HBOT in improving bone health. However, the optimal HBOT regimen for treating various bone diseases still requires further definition to expand the indications for its clinical application. This paper outlines the mechanisms of HBOT, focusing on its antioxidant stress, promotion of bone vascularization, and anti-inflammatory properties. The paper also describes the application of HBOT in orthopedic diseases, thereby providing a scientific basis for the development of precise and personalized HBOT treatment regimens in clinical orthopedics.

Keywords: bone; bone formation; bone resorption; hyperbaric oxygen therapy.

Figure 1

Mechanisms underlying the therapeutic effects of HBOT in bone-related disorders. HBOT enhances bone formation, inhibits resorption, promotes vascularization, mitigates oxidative stress, and suppresses inflammation. These effects collectively support its efficacy in treating conditions such as osteoporosis, diabetic bone disease, bone defects, Bone nonunion, osteoradionecrosis, avascular necrosis of the femoral head, and osteomyelitis.

Figure 2

Molecular mechanisms of HBOT in bone homeostasis regulation. HBOT maintains bone homeostasis by balancing osteoblast-mediated bone formation and osteoclast-mediated resorption. It enhances osteoblast proliferation, differentiation, and mineralization through the FGF-2/MEK/ERK, Akt/p70/NF-κB, and PKC/JNK signaling pathways. HBOT also modulates the OPG/RANK/RANKL axis, increasing OPG’s antagonistic effect on RANKL to promote bone formation, while downregulating RANK to inhibit osteoclastogenesis and resorption. Furthermore, HBOT reduces HIF-1α to promote bone formation and suppresses HIF-2α to inhibit bone, resorption.

Figure 3

Molecular mechanisms of HBOT in bone healing and angiogenesis. HBOT significantly upregulates the expression of VEGF and BMP-2, promoting early bone formation, mineralization, and bone remodeling. Additionally, HBOT enhances bone volume and type H vessel formation around the cranial bone graft in mice, stimulating the proliferation of mature osteoblasts and endothelial cells via the angiopoietin-2 and integrin α5β1 signaling pathways. HBOT also downregulates the elevated expression of S100A9 associated with ANFH, reducing endothelial cell apoptosis and improving vascular function. Moreover, HBOT decreases pro-inflammatory cytokines IL-1 and IL-6, leading to a significant increase in CD31-positive endothelial cells and creating an anti-inflammatory microenvironment conducive to bone regeneration.

Figure 4

Redox regulation mechanisms of HBOT in bone homeostasis and repair. HBOT significantly improves bone homeostasis and repair by modulating the redox state. First, HBOT upregulates SOD levels, inhibiting the expression of RANKL, CTX-1, and MDA, thereby alleviating bone loss. Second, HBOT activates the Nrf2 and its downstream pathways, suppressing MYC expression and reducing RANKL levels. Additionally, through the upregulation of Nrf2, HBOT inhibits the expression of NFATc1, TRAP, and Ctsk, further suppressing osteoclast activity. Moreover, the upregulation of Nrf2 reduces NF-κB activity, mitigates ROS accumulation, and inhibits osteoclast differentiation and function. Concurrently, HBOT enhances HO-1 expression, promoting osteoblast activity and accelerating bone formation and repair.

Figure 5

Modulation of the bone microenvironment by HBOT through anti-inflammatory mechanisms. HBOT significantly reduces pro-inflammatory cytokines TNF-α and IL-6, exerting a positive effect on the bone microenvironment. In the early stages of AVNFH, HBOT lowers plasma TNF-α and IL-6 levels, demonstrating its anti-inflammatory action. In obesity and premature aging models, HBOT reduces plasma TNF-α and IL-6 levels, preventing age-related bone loss.