Osteoporosis is a disease of the skeletal system with degradation of bone tissue microstructure and low bone mineral density (BMD), which usually results in an increased risk of bone fragility and fractures (1). It is estimated that there are 1.5 million osteoporosis-related fractures per year in the US. Fractures can lead to a poor quality of life, a dependent living situation, increased fracture-related mortality, and medical care costs. Furthermore, especially in older adults, hip fractures can be devastating (2). Given the adverse consequences of osteoporosis-related diseases such as fractures, the prevention and management strategies for osteoporosis are of great significance and necessary.

The risk factors that contribute to reduced BMD and osteoporosis are multiple, including genetic, hormonal, environmental, and lifestyle-related factors (3–6). In recent years, various micronutrients, such as magnesium (Mg), have been reported to play an essential role in musculoskeletal diseases. On the one hand, Mg is an essential cofactor for enzymes related to bone matrix synthesis, which promotes bone formation by stimulating osteoblast proliferation. On the other hand, Mg deficiency affects parathyroid hormone (PTH) and Vitamin D levels while promoting inflammatory cytokine secretion and enhancing osteoclast activity (7, 8). However, the results of observational studies about the relationship between dietary Mg intake and osteoporosis were contradictory. Orchard et al. (9) reported that lower dietary Mg intake was related to lower BMD of the hip and whole body, and Ryder et al. (10) found a similar result in white women and men. Moreover, meta-analyses from Farsinejad-Marj et al. (11) and Groenendijk et al. (12) showed that dietary Mg intake was positively correlated with BMD of the femoral neck and total hip. However, no significant associations were found between dietary Mg intake and BMD at other sites. In a study with 2.8 years of follow-up, Kaptoge et al. (13) found that dietary Mg intake was not associated with hip BMD in both men and women, which was supported by Chan et al. (14) and Woo et al. (15).

In addition, previous studies have mainly focused on the effect of dietary Mg intake levels on osteoporosis but ignored the effective bioavailability of dietary Mg. The Mg depletion score (MDS) is a novel scoring tool that integrates several common factors affecting the absorption and excretion of dietary Mg in the US population (8, 16–18). The MDS has been shown to reflect the systemic utilization of the dietary Mg and can identify individuals with relatively low dietary Mg utilization. The higher score represented a lower bioavailability of dietary Mg. Moreover, Fan et al. (19) used the Mg tolerance test to validate MDS as a predictor of real body Mg deficiency in US adults. The results showed that the model containing the MDS alone had the highest area under the receiver operating characteristic curve estimator among models with single predictors, including serum and urine Mg. Thus, MDS may more accurately reflect the real Mg deficiency state of the body. To our knowledge, no previous studies are exploring the relationship between MDS and osteoporosis.

Given the above background, the purpose of the current study was to identify the relationship between dietary Mg intake and osteoporosis and further explore the association between MDS and osteoporosis in US adults.

According to the representative sample of U.S. adults in the National Health and Nutrition Examination Survey (NHANES), we demonstrated that dietary Mg intake levels and osteoporosis were negatively correlated, especially in participants aged 55 years or older. This result suggests that adequate dietary Mg intake may be a factor that prevents osteoporosis in older adults. In addition, we proved that MDS generally presented a significantly positive relationship with osteoporosis. The results of subgroup analyses showed that for males, the positive association mainly presented in the middle Mg intake group. For females, the positive associations mainly presented in both low and middle Mg intake groups. To our knowledge, this is the first study to combine the dietary Mg intake with the bioavailability of Mg and comprehensively explore the association between MDS and osteoporosis.

As we all know, Mg is an essential mineral involved in bone metabolism (7, 8). However, more than half of US adults do not meet the estimated average requirement (EAR) or RDI of daily Mg intake (23, 24). In the present study, the mean daily dietary Mg intake levels were 304.5164 mg ± 126.4613 mg in males and 263.1411 mg ± 114.2658 mg in females (Table 1) and were also far below EAR and RDI. Dietary Mg mainly comes from green vegetables, unpolished grains, nuts, and shellfish, and Mg content in food is easily lost during cooking and refining processes. Moreover, western diets are often rich in refined foods while deficient in green vegetables, and this may help explain the widespread dietary Mg deficiency in the US (25). Given the prevalence of dietary Mg deficiency in the US and the essential role of dietary Mg plays in the bone, comprehensively evaluating the relationship between dietary Mg intake levels and osteoporosis in the US is necessary. The present study showed a negative effect of dietary Mg intake deficiency on the prevention of osteoporosis, which was supported by the results of several previous literature (9–12). To better characterize the relationship in detail, we also performed a two-piecewise linear regression model and a recursive algorithm to find the inflection points of dietary Mg intake in the subgroups with a significant relationship. In the participants aged 55 years or older, the inflection points were 138.0 mg for males and 337.5 mg for females (Table 3). From the perspective of preventing osteoporosis, we recommend that the subpopulation whose daily dietary Mg intake was below the inflection point should be more alert to osteoporosis.

When exploring the effect of dietary Mg on osteoporosis, the bioavailability of dietary Mg should also not be ignored. Clinically, serum Mg is routinely used to diagnose systemic Mg deficiency. However, Mg in the human body is mainly stored in bones and soft tissue (26). Serum Mg only accounts for 0.3% of the whole body Mg content (27). Previous studies have shown that serum Mg was not sensitive to a decline in the actual Mg stores of the body. In addition, individuals with normal serum Mg may have Mg deficiency and respond to Mg supplementation (28, 29). Compared with other methods, the Mg tolerance test (MTT) is more accurate in evaluating the systemic Mg status (30). The test requires measuring the Mg level in 24 h urine and then performing an intravenous drip of Mg for 4 h and collecting the second 24 h urine. However, the relatively complex process limits its widespread application (19, 30, 31). Therefore, an accurate, simple, and convenient tool that can be widely used to evaluate the bioavailability of dietary Mg is urgently needed. The absorption and excretion of dietary Mg can be affected by several factors. For instance, alcohol abuse can lead to a rapidly increased excretion of urinary Mg (18, 32). Proton pump inhibitors (PPIs) can reduce intestinal Mg absorption by interfering with the activity of epithelial Mg²⁺ transient receptor potential channel subfamily M, member 6, and the use of thiazide and loop diuretics were also proved to result in a Mg deficiency (16). In addition, plasma Mg homeostasis is primarily regulated by the kidneys, which are responsible for over 80% of the ultrafiltration and reabsorption of plasma Mg (33). Thus, renal insufficiency of various causes can also affect Mg reabsorption (8). Fan et al. (19) found that Mg levels as determined by MTT had a significant correlation with estimated glomerular filtration rate (eGFR), and Mg deficiency is positively correlated with the severity of renal insufficiency. As a reflection of the Mg bioavailability, MDS combined all the above factors. Meanwhile, the higher the MDS, the poorer the bioavailability of dietary Mg. The accuracy of MDS as a predictive tool for systemic Mg deficiency has been validated by MTT (19).

This study comprehensively assessed the relationship between MDS and osteoporosis. In subgroup analyses based on dietary Mg intake levels, this study found that MDS positively correlated with osteoporosis in the low and middle dietary Mg intake levels. Furthermore, when adding sex to the stratification factor, the positive associations remain stable in the male-middle intake, female-low, and female-middle intake groups. However, this relationship was not significant in the male and female-high intake groups. Similarly, the percentage of participants whose daily dietary Mg intake below RDI was higher in the osteoporosis group, but when daily dietary Mg intake was above RDI or UL, the result seemed to be the opposite. Given that this study used a daily dietary Mg intake of 337.5 mg as the cut-off point for the middle and high groups, which were close to the daily RDI of a US adult (23, 34), these findings may indicate the following three points: (1) in the case of inadequate dietary Mg intake, insufficient Mg bioavailability by the body may further increase osteoporosis, especially in people whose daily dietary Mg intake is below the RDI; (2) the adverse effect of insufficient Mg bioavailability on bone appeared to be partially eliminated by the adequate intake of dietary Mg; and (3) from the perspective of preventing osteoporosis, when dietary Mg intake is below the RDI, increasing dietary Mg intake is beneficial. However, when the dietary Mg intake exceeds the RDI or even reaches the UL, the effect on preventing osteoporosis may deserve further exploration.

There are several strengths in our study. First, we used a large nationally representative database collected via standardized protocols to minimize possible bias. Secondly, we adequately controlled for confounders and performed subgroup analyses according to different stratification variables to make the study results more rigorous. In addition, our study has some potential limitations. First, since the present study was an across-sectional analysis, the evidence for a causal relationship may not be sufficient. In the future, more prospective studies need to be performed to confirm the results in the present study. Second, the data collected from the questionnaires and interviews may result in recall bias. Third, although we have adjusted some covariates, other unmeasured confounding factors may also lead to potential bias. Lastly, vitamin D metabolism is dependent on Mg as a cofactor (35), and metabolic balance between PTH and vitamin D has been shown to be closely related to osteoporosis (36). Therefore, dietary Mg deficiency may affect osteoporosis (37) by altering the balance between vitamin D metabolite and PTH. The present study was unable to verify this mechanism due to lack of information on PTH and vitamin D.

This study indicated that in people with a daily intake of Mg level below the recommended daily intake (RDI), the dietary Mg intake and Mg bioavailability represented by MDS have a negative correlation with osteoporosis. According to the results, the combination of MDS and dietary Mg intake may be more comprehensive and rigorous in screening the osteoporosis population. Therefore, early monitoring and interventions for osteoporosis may be necessary for those with insufficient dietary Mg intake or high MDS scores.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

JW, FX, and NS: conceptualization and investigation. JW: methodology, analysis, and writing—original draft. JW, FX, NS, and ZX: writing—review and editing. All authors contributed to the development of this manuscript and read and approved the final version.

This work was supported by the National Natural Science Foundation of China (31870961), the International Cooperation Project of the Science and Technology Department of Sichuan Province (Grant No. 2022YFS0099), and Clinical Research Incubation project of West China Hospital of Sichuan University (2019HXFH041).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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