Imbalance of Osteoprotegerin/Receptor Activator of Nuclear Factor-kB Ligand and Oxidative Stress in Patients with Obstructive Sleep Apnea-Hypopnea Syndrome
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a sleep disorder characterized by repeated episodes of apneas or hypopneas due to upper airway narrowing, leading to chronic intermittent hypoxia (CIH). CIH resembles the ischemia-reperfusion process, generating excess oxygen free radicals through repeated hypoxia and reoxygenation, which causes an imbalance between pro-oxidative and anti-oxidative mechanisms, leading to oxidative stress. This oxidative stress is considered a key mechanism underlying the systemic damages associated with OSAHS. OSAHS is linked to various systemic diseases, including cardiovascular diseases, diabetes, and osteoporosis. While it is generally recognized that OSAHS is associated with a higher incidence of osteoporosis, the molecular mechanisms underlying this association remain speculative. Oxidative stress is believed to play a significant role in this pathophysiological process, and hypoxia itself may influence bone metabolism by disrupting the balance between osteoblasts and osteoclasts.
Bone metabolism is regulated by a delicate balance between osteoprotegerin (OPG) and receptor activator of nuclear factor-kB ligand (RANKL). RANKL is a cytokine that promotes osteoclast differentiation and activation by binding to its receptor RANK, stimulating the formation of mature osteoclasts. OPG, on the other hand, acts as a decoy receptor for RANKL, inhibiting bone resorption by down-regulating RANKL signaling. The balance between OPG and RANKL is crucial for maintaining normal bone remodeling. An imbalance in this system can lead to increased bone resorption and osteoporosis. Previous studies have shown that oxidative stress and systemic inflammation, both of which are prominent features of OSAHS, can disrupt the OPG/RANKL balance, potentially contributing to bone loss.
This study aimed to investigate the changes in RANKL, OPG, oxidative stress, and bone metabolism markers in patients with OSAHS to understand the potential mechanisms underlying bone loss in this population. The study enrolled 48 male patients with OSAHS, confirmed by polysomnography (PSG), and 20 male controls without OSAHS. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry (DXA) at the lumbar spine and femoral neck. Blood samples were collected to measure serum levels of RANKL, OPG, bone-specific alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP-5b), and total antioxidant capacity (TAOC).
The results showed that the BMD and T-scores of the femoral neck and lumbar spine were significantly lower in the OSAHS group compared to the control group, indicating increased bone loss in OSAHS patients. The serum level of BAP, a bone formation marker, was significantly decreased in the OSAHS group, while the level of TRAP-5b, a bone resorption marker, did not differ between the two groups. This suggests that decreased bone formation, rather than increased bone resorption, may be the primary mechanism of bone loss in OSAHS. Furthermore, the serum levels of OPG and the OPG/RANKL ratio were significantly lower in the OSAHS group, indicating an imbalance towards osteoclastogenesis. The TAOC level, a marker of anti-oxidative capacity, was also significantly decreased in the OSAHS group, suggesting an imbalance between oxidative stress and anti-oxidative capacity in these patients.
Correlation analysis revealed that the TAOC level was positively correlated with BAP in the OSAHS group, suggesting that oxidative stress may play a role in decreased bone formation. However, no significant correlations were found between TAOC and BMD or T-scores, or between OPG (or the OPG/RANKL ratio) and BMD or TAOC. These findings suggest that while oxidative stress may contribute to bone loss in OSAHS through its effects on bone formation, the role of the OPG/RANKL imbalance in bone metabolism in OSAHS requires further evaluation.
The study also highlighted the potential role of hypoxia in abnormal bone metabolism in OSAHS. Hypoxia has been shown to enhance osteoclast activity and increase bone resorption. Studies have demonstrated that hypoxia inhibits osteoblast proliferation and differentiation, leading to decreased bone formation. The chronic intermittent hypoxia experienced by OSAHS patients may therefore contribute to bone loss through both increased bone resorption and decreased bone formation.
Several limitations of the study were noted. First, significant correlations were not observed between the OPG/RANKL ratio and TAOC levels in OSAHS patients, so the association between oxidative stress and the OPG/RANKL imbalance could not be confirmed. Second, the cross-sectional nature of the study means that changes in OPG/RANKL, TAOC, and bone metabolism markers after treatment for OSAHS were not evaluated. Further studies are needed to explore these changes. Finally, the study included only male subjects, and the results may not be generalizable to females or non-smokers. Larger studies including both genders and non-smokers are needed to fully understand the bone metabolism status and mechanisms of osteoporosis in OSAHS.
In conclusion, this study demonstrated that OSAHS patients have lower levels of TAOC, which are associated with decreased bone formation, suggesting a role of oxidative stress in bone loss. The imbalance in the OPG/RANKL system observed in OSAHS patients may also contribute to abnormal bone metabolism, although further research is needed to confirm this relationship. The findings highlight the importance of addressing oxidative stress and bone metabolism in the management of OSAHS patients, particularly those at risk for osteoporosis.
doi.org/10.1097/CM9.0000000000000046
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