Obstructive sleep apnea (OSA) is a prevalent and potentially life-threatening sleep disorder affecting an estimated 936 million adults aged 30–69 years worldwide, contributing significantly to global morbidity and healthcare costs (1, 2). Anatomical factors are fundamental to OSA pathogenesis. Dempsey et al. established that variations in upper airway structure and collapsibility play a central role in sleep-disordered breathing, even in non-clinical populations (3). Characterized by repetitive upper airway collapse during sleep, OSA leads to intermittent hypoxemia, sleep fragmentation, and an increased risk of cardiovascular disease, metabolic dysfunction, and neurocognitive impairment (4–8). The economic burden of OSA extends far beyond direct treatment costs, with recent analyses indicating that OSA-related comorbidities and consequences impose healthcare expenditures exceeding €30 billion annually in developed countries, underscoring its substantial impact (9). Recent findings by Gong et al. revealed that body mass index (BMI) serves as a mediator in the link between serum vitamin D levels and sleep deprivation, emphasizing the need to consider metabolic status when assessing the influence of nutritional factors on sleep (10). While traditional risk factors include obesity, male sex, and advancing age (11–14), emerging evidence suggests that nutritional deficiencies may contribute to OSA pathogenesis through mechanisms involving upper airway muscle function, inflammatory pathways, and respiratory control (15–19).

Vitamin D deficiency (VDD), defined as 25-hydroxyvitamin D levels below 20 ng/mL (20), affects approximately 35% of people globally and has been implicated in various respiratory conditions beyond its classical role in bone metabolism (21–24). Mechanistically, vitamin D receptors are widely distributed throughout the respiratory muscles, and VDD may impair upper airway dilator muscle function, increase systemic inflammation, and alter immune responses that could predispose to OSA development (19, 25). While evidence suggests an association between vitamin D status and OSA risk, most studies have been cross-sectional in design, failing to establish temporal relationships and providing limited evidence for causality (26–28). Recent prospective evidence from the UK Biobank demonstrated an inverse association between serum 25-hydroxyvitamin D concentrations and new-onset OSA, particularly in individuals with obesity (29). However, significant knowledge gaps remain, including limited population diversity, uncertain dose–response relationships across different VDD severities, and incomplete understanding of effect modification by demographic and clinical factors beyond obesity. Additionally, while the UK Biobank study provided valuable long-term evidence with a 12-year follow-up (29), it lacked shorter-term outcome assessments that could inform immediate public health intervention strategies.

Given the high prevalence of both VDD and OSA, establishing whether VDD is a modifiable risk factor for OSA development has significant clinical and public health implications. This multi-institutional retrospective study utilized the TriNetX federated health research network to examine the association between sustained VDD and subsequent OSA development in a large, well-characterized patient population using rigorous propensity score matching. We hypothesized that patients with confirmed VDD would demonstrate an increased risk of developing OSA compared to vitamin D-sufficient controls, with potential dose–response relationships and differential effects across patient subgroups.

This large-scale multi-institutional retrospective study demonstrates that patients with sustained VDD faced an increased hazard for OSA development over 5 years. This association demonstrated temporal consistency, a dose–response relationship, and variation across clinically relevant subgroups, supporting a potential causal link. In subgroup analyses, the vitamin D-OSA association was most pronounced in women, younger adults, and individuals with elevated BMI but showed no significant effect in normal-weight individuals. Beyond OSA, VDD is associated with an increased risk of insomnia and hypersomnia, but not circadian rhythm disorders, suggesting specificity in sleep-related pathophysiological mechanisms.

The relationship between vitamin D status and OSA has garnered increasing attention, with accumulating evidence suggesting both cross-sectional associations and potential mechanistic links (26–28). Previous systematic reviews and meta-analyses have consistently demonstrated lower serum 25-hydroxyvitamin D levels in patients with OSA than in controls (26–28). However, most previous studies have been limited by their cross-sectional designs, small sample sizes, and inadequate control for confounding variables, making it difficult to establish temporal relationships or infer causality. Mechanistically, vitamin D support the potential role of vitamin D in OSA pathogenesis is supported by several biological pathways (19, 25). Vitamin D receptors are widely distributed throughout the respiratory muscles, including the upper airway dilator muscles, and deficiency may impair muscle function and reduce upper airway stability during sleep (19, 25). Additionally, vitamin D plays a crucial role in immune regulation and inflammatory pathways, with deficiency associated with increased systemic inflammation that could contribute to upper airway edema and collapsibility (19, 25). The landmark UK Biobank study provided the first large-scale prospective evidence, demonstrating an inverse relationship between serum 25-hydroxyvitamin D concentrations and new-onset OSA over 12 years of follow-up, particularly in individuals with obesity (29).

Our findings demonstrate remarkable temporal consistency in the vitamin D-OSA association across multiple follow-up intervals, suggesting that VDD confers an early and sustained increased risk rather than delayed effects. This consistent temporal pattern supports a potential causal relationship, as random associations are likely to vary across different follow-up periods. The early manifestation of risk within the first year has important clinical implications, suggesting that vitamin D status assessment and potential supplementation may be relevant for short-term OSA prevention strategies. Perhaps the most compelling evidence for a causal relationship comes from our demonstration of a clear dose–response effect. Patients with severe VDD faced a substantially higher OSA risk than those with moderate deficiency, indicating that the relationship is not simply threshold-dependent but exhibits true biological gradation. Such dose–response relationships are considered one of the strongest criteria for establishing causality in observational studies. Our findings align with and substantially extend the UK Biobank results (29), providing novel contributions, including demonstration across diverse healthcare networks, implementation of a three-month washout period to reduce misclassification bias, and requirement for confirmatory vitamin D measurements ensuring sustained deficiency rather than transient low levels.

Our demonstration of significant effect modification across demographic and clinical subgroups represents a novel and potentially paradigm-shifting finding with implications for both mechanistic understanding and clinical practice. The significantly stronger vitamin D-OSA associations in women than in men suggest that vitamin D may interact with hormonal or physiological factors that vary between sexes. Several mechanisms could explain this observation, including higher vitamin D-binding protein levels in women affecting bioavailable vitamin D concentrations, estrogen influences on both vitamin D metabolism and upper airway muscle function, and sex-specific anatomical and physiological determinants of OSA that may be differentially sensitive to vitamin D status (34–36). The striking inverse relationship between age and vitamin D sensitivity represents another novel finding, with younger adults demonstrating a dramatically increased OSA risk compared to older patients. This pattern suggests that VDD may be particularly detrimental during periods of active tissue development and maintenance, with younger individuals potentially having greater vitamin D receptor density and responsiveness. Perhaps the most clinically significant subgroup finding is the complete absence of a vitamin D-OSA association in normal-weight individuals, in contrast with the substantial risk in overweight/obese patients. This interaction suggests that VDD may specifically potentiate obesity-related OSA mechanisms rather than acting as an independent risk factor, with implications including the role of vitamin D in adipose tissue inflammation, metabolic dysfunction, and insulin resistance.

Our multivariable analysis identified VDD as an independent predictor of OSA and clarified its relative contribution alongside established risk factors. Obesity has emerged as the dominant risk factor with overwhelming impact, confirming its central role in OSA pathogenesis and reinforcing that weight management remains the most critical intervention for OSA prevention and treatment. Respiratory comorbidities demonstrate a substantial OSA risk, likely reflecting shared pathophysiological mechanisms, including chronic inflammation and altered respiratory mechanics that predispose to upper airway instability during sleep (37, 38). The emergence of COVID-19 as a significant predictor of OSA in our study aligns with recent findings by Lin et al. (39), who demonstrated that individuals with a history of SARS-CoV-2 infection had a substantially elevated risk of developing OSA during a 12-month follow-up period (HR: 1.57). This contemporary association may reflect the long-term respiratory sequelae of COVID-19, including persistent inflammation, upper airway dysfunction, and post-infectious respiratory compromise. Male sex conferred an increased risk, consistent with established epidemiological patterns reflecting anatomical, hormonal, and behavioral differences (14). Despite adjustment for these multiple confounders, VDD retained a significant association, indicating genuine pathophysiological relevance rather than confounding by other risk factors.

Our analysis extends beyond OSA to explore the broader impact of vitamin D on sleep health, revealing disorder-specific associations that offer mechanistic insights. Insomnia showed a consistent association with VDD across all follow-up periods, with stronger links observed in cases of severe deficiency, suggesting a dose–response relationship comparable to that seen with OSA. The vitamin D-insomnia association aligns with growing evidence for the role of vitamin D in sleep regulation through multiple pathways, including vitamin D receptors in brain regions involved in sleep–wake control and vitamin D’s anti-inflammatory effects that may influence sleep quality through modulation of cytokine pathways affecting sleep architecture (40–42). Hypersomnia showed weaker and less consistent associations, with significant effects that diminished over longer follow-up periods, suggesting that VDD may contribute to the early manifestations of excessive daytime sleepiness through mechanisms involving sleep quality and restorative sleep processes. Notably, circadian rhythm sleep disorders showed no significant association with vitamin D status, suggesting that while vitamin D influences sleep quality and respiratory control during sleep, it may not substantially affect the timing and entrainment of circadian rhythms in clinical populations.

Recent critical reviews have highlighted a complex bidirectional relationship between the vitamin D status and OSA development. Schiza et al. (43) emphasized that while there is growing evidence supporting the role of vitamin D in sleep maintenance and regulation, the fundamental question of causality remains unresolved: whether VDD increases OSA risk or OSA itself predisposes to VDD. This uncertainty underscores the importance of our study design with temporal sequencing and washout periods to strengthen causal inference. The meta-analysis by Serafin et al. (44), which excluded patients with comorbidities, reinforces our findings by showing that the vitamin D–OSA association is independent of systemic confounders. Their focus on otherwise healthy populations supports our observation that VDD may be an independent risk factor rather than merely a consequence of OSA-associated comorbidities. Our study extends these findings by demonstrating that sustained VDD precedes OSA development in a large, well-matched cohort, with consistent effects across multiple follow-up intervals.

Several limitations of our study should be acknowledged when interpreting our findings. First, as this was a retrospective observational study using electronic health records, we could not establish definitive causality despite the temporal sequence and dose–response relationships observed. Unmeasured confounding variables, including dietary patterns, physical activity levels, and socioeconomic factors, may influence both vitamin D status and OSA risk. Second, our reliance on ICD-10 diagnostic codes for outcome ascertainment may introduce misclassification bias because OSA diagnosis in clinical practice varies in accuracy and may be influenced by healthcare access, physician awareness, and patient symptom presentation. Third, vitamin D supplementation, although captured as a baseline characteristic, was not incorporated into stratified analyses or adjusted as a time-varying covariate owing to the limitations of the TriNetX dataset, which lacks reliable information on supplement dosage, duration, adherence, and initiation timing. We opted not to exclude patients who had received supplements, as doing so could introduce selection bias and limit generalizability. However, we recognize that the inability to fully account for supplementation introduces residual confounding, and future studies with more granular data on supplementation patterns are warranted. Fourth, although the TriNetX database provides substantial statistical power and diverse populations, it may not be fully representative of all demographic groups or healthcare systems, potentially limiting its generalizability to resource-limited settings. Finally, our study period encompassed the COVID-19 pandemic, which may have affected both healthcare utilization patterns and sleep disorder diagnosis rates.

This study demonstrated an independent association between VDD and an increased risk of developing OSA, supported by temporal consistency, dose–response relationships, and biologically plausible effect modification. Our novel finding that vitamin D effects are most pronounced in women, younger adults, and overweight/obese individuals has important implications for personalized risk assessments and targeted intervention strategies. From a clinical perspective, our findings suggest that vitamin D status assessment may be valuable as part of a comprehensive OSA risk evaluation, particularly in women, younger adults, and individuals with an elevated BMI. Future research should focus on randomized controlled trials to definitively establish whether vitamin D supplementation can prevent OSA development, particularly in the high-risk subgroups identified in our analysis.