Diabetes mellitus is a collection of common metabolic endocrine diseases characterized by abnormalities of glucose and fat metabolism, as well as elevated plasma glucose [1]. According to the World Health Organization, more than 463 million people worldwide had diabetes in 2015, and this figure is expected to double by 2040 as the population ages [2]. Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, accounting for more than 90% of the diabetic population and affecting nearly 22% of older adults in the United States [3].

Bone mineral density (BMD) is a quantifiable measure of bone mass and strength, determined by the mineral content in bone tissue [4]. It can be used for the diagnosis of osteoporosis, to predict the risk of fractures, and to assess the efficacy of drug therapy. Osteoporosis is a condition that affects the entire skeletal system, causing reduced bone density and deterioration of bone structure, leading to increased vulnerability to fractures [5]. With an ageing global population and changing lifestyle habits, the increasing incidence and associated socio-economic burden of osteoporosis worldwide have become a critical public health issue [6]. It is estimated that 10.2 million Americans over the age of 50 suffered from osteoporosis and 43.4 million suffered from osteopenia in 2010 [7].

T2DM and osteoporosis have similar risk factors and common pathophysiological characteristics. The two often coexist, which can exacerbate each other, thus worsening the prognosis of patients and increasing mortality. T2DM is known to affect the metabolism of sugar, fat and protein, as well as causing imbalances in calcium, phosphorus and magnesium, and subsequently promoting a range of complications such as neuropathy, cardiovascular disease (CVD), peripheral vascular disease, retinopathy and metabolic bone disease [8, 9]. Certain medications used to control high blood sugar may exacerbate bone complications. There is also an association between diabetic complications and risk for falls and subsequent fractures in osteoporosis [10]. As a result, patients with T2DM are at a high risk for osteoporosis, with approximately one-third having combined osteoporosis [11]. Brittle fractures caused by osteoporosis have become an important cause of death and disability in patients with T2DM [12].

Although previous studies have looked into the relationship between osteoporosis and chronic diseases such as CVD and cancer, the majority of these studies have focused on women who have had osteoporotic fractures, postmenopausal women, or the elderly, with a particular emphasis on the relationship between osteoporosis and the incidence of CVD [13, 14, 15]. The coexistence of osteoporosis and T2DM is becoming more common with age and lifestyle changes, which influences patients’ disability and mortality [16]. Nevertheless, the associations of a reduced BMD value with CVD and all-cause mortality in T2DM patients have not been definitively proven. Neglecting the potential link between these diseases could have serious consequences. It is crucial to delve into further research in order to ascertain the precise relationship between these risk factors, allowing for the implementation of effective preventive measures to reduce disease risks. As a result, a large cohort research study involving this specific demographic is required, as well as a more in-depth review of the influence on CVD and mortality risk.

In this study, we used the National Health and Nutrition Examination Survey (NHANES) to evaluate the relationship between BMD and the risk of CVD and all-cause death in the US population with T2DM.

Analyzing data from NHANES 2005–2010 and 2013–2014, we found a strong correlation between higher BMD and lower mortality rates for both all causes and CVDs in American adults diagnosed with T2DM. Furthermore, our research revealed that osteoporosis and osteopenia were linked to a higher risk of all-cause and CVD mortality in T2DM patients during long-term monitoring, even after adjusting for multiple variables, and stratified analysis in relation to mortality from CVD. Prior research has indicated that the association between osteopenia and osteoporosis and the risk of all-cause mortality and CVD mortality is still a topic of debate. According to the study by Cai S et al. [21], individuals with osteoporosis in various parts of the body such as the total femur, femur neck, and intertrochanter had a greater risk of all-cause mortality compared to those without osteoporosis. Significant L-shaped relationships were found only for mortality in heart disease with BMD increments found within specific femur limits, but these relationships disappeared as BMD continued to rise [21]. Additional results from cohorts representing the entire nation also indicated that osteoporosis was linked to a higher chance of death from any cause (HR = 1.37, 95% CI = 1.11–1.68), particularly among older individuals with lower BMI. There was no significant association between osteoporosis and CVD mortality, which could be attributed to the limited number of CVD and cancer deaths, as well as the short duration of follow-up [22]. Other studies have found some positive associations on the relationship between osteoporosis and CVD risk. The study by Rodríguez-Gómez et al. [23], which included a total of 305,072 UK Biobank participants diagnosed with osteoporosis at baseline, found that men with osteoporosis had a higher mortality risk from CVD (HR = 1.68, 95% CI = 1.19–2.37). However, women with osteoporosis only had a higher risk of incident CVD (HR = 1.24, 95% CI = 1.97–1.44), and the risk of CVD mortality was not affected [23]. Calcaneal quantitative ultrasound (QUS) was utilized to assess bone material properties, particularly in elderly women, and could also be used to diagnose osteoporosis. In a prospective study of aged women, Gebre et al. [24] discovered that quantitative ultrasound measurements of the calcaneus were independently associated with increased cardiovascular and all-cause mortality, regardless of established cardiovascular risk factors. Reducing broadband ultrasound attenuation (BUA) in the minimally and multivariable adjusted model including cardiovascular risk factors increased the relative hazard for all-cause mortality (HR = 1.15, 95% CI = 1.06–1.261) and CVD mortality (HR = 1.20, 95% CI = 1.04–1.38). Nonetheless, this observational study was limited to only geriatric females, and the results were not derived from the analysis of BMD values [24]. In a similar study called the AA-DHS, vertebral BMD (vBMD) was analyzed in 675 African American men with T2DM and the results suggested that lower vBMD was associated with increased all-cause mortality [25]. However, this study also showed that lower vBMD was not linked to other mortality risk factors, including subclinical atherosclerosis [25]. In light of this, we embarked on a comprehensive study to determine the relationship between BMD and all-cause mortality and CVD mortality across multiple anatomical sites. Our investigation showed the independent and incremental value of low BMD, particularly with osteoporosis in assessing the risk of CVD in adults with T2DM. Our findings in T2DM contribute to the existing literature on this subject.

Diabetes mellitus has been linked to impaired bone quality and increased risk of fracture [26]. The pathophysiology of osteoporosis caused by T2DM is multifactorial, involving reduced bone formation, osteoblast dysfunction, and low bone turnover [27]. Hyperlipidemia, impaired insulin signaling, low levels of insulin-like growth factor 1, reactive oxygen species generation, and inflammation are all linked to diabetes and hyperglycemia, and may all contribute to the inhibition of osteoblast activity [28, 29, 30, 31]. Degraded bone quality and microarchitectural defects are the result of multiple factors, including chronic hyperglycemia and skeletal advanced glycation end products (AGES), which irreversibly accumulate from the nonenzymatic addition of sugar moieties to the amine groups of proteins. AGES negatively impacted skeletal integrity, particularly type 1 collagen [32, 33, 34, 35, 36, 37]. T2DM and osteoporosis are two extremely common adverse conditions of CVD, and share several risk factors involved in their pathophysiological mechanisms, including aging, smoking, weight gain, inactivity, estrogen deficiency, hyperlipidemia, oxidative stress, chronic inflammation and common polygenes [38, 39, 40, 41, 42]. Therefore, an increase in bone loss in this particular T2DM population is strongly associated with an increase in the risk of cardiovascular and all-cause mortality.

It is worth noting that in the sensitivity analysis, when we only retained T2DM patients with no prior history of acute CVD, such as heart failure, angina pectoris, coronary heart disease, myocardial infarction, and stroke, the increased risk of CVD mortality in T2DM patients with reduced bone mass was not significant compared to normal bone mass patients, but the increased risk of CVD mortality in T2DM patients with osteoporosis remained stable. This suggests that the increased risk of mortality directly caused by developing CVD was only significant when bone mineral content was extremely low, and it also confirmed that osteoporosis was closely associated to both CVD incidence and CVD mortality risk. Due to the limitations of the NHANES database, specific analysis of HbA1c levels in T2DM patients was not conducted in this study, which may affect the accuracy of the study results. However, in a retrospective cross-sectional study involving 856 male T2DM patients, HbA1c and insulin use did not differ significantly between CVD and non-CVD individuals [43], and another study concluded that age-adjusted HbA1c was not a risk factor for osteoporosis in postmenopausal women with T2DM [44]. In addition, this study did not evaluate parameters related to calcium metabolism disorders such as blood phosphorus, vitamin D, and parathyroid hormone, which are potential mediators between osteoporosis and CVDs. Only total blood calcium was included in the confounding factors for correction, which may make the study results one-sided.

In stratified analyses, our study found that the independent associations of osteoporosis and osteopenia with an increased risk of CVD mortality were stronger in participants with wider waist and higher TG levels, possibly because the wide waist and high TG levels were themselves independent risk factors for adverse cardiovascular outcomes in T2DM. Our results showed that patients with osteopenia and osteoporosis, in addition to research by Yang and Shen [45], found a link between BMI and lumbar vertebral and femoral neck BMD. Zhao et al. [46] found a favorable correlation between HDL-C levels and BMD, as well as a preventive impact against osteoporosis (OR = 0.07, 95% CI = 0.01, 0.53, p 0.05). This was consistent with our findings. However, the link between TC and TG levels and osteoporosis remained inconclusive. In a previous study, low BMD was associated with atherosclerotic lipid abnormalities [47], but this association was not consistently seen in other studies. A recent meta-analysis suggested that among subjects who were not taking lipid-lowering drugs, TC and TG in osteopenia were not significantly increased or decreased [48]. These factors were generally considered to be protective factors for CVD, which was exactly the opposite of our findings. To explain this phenomenon, we believe that diabetes-induced osteoporosis represents the combined impact of conventional osteoporosis with the additional fracture burden attributed to diabetes, not just the impaired bone quality. T2DM patients had a significantly increased risk of fracture, as well as an increased risk of complications following fracture, such as delayed wound closure, infectious, and peri-operative cardiovascular events [49, 50]. Therefore, this might be the reason why even though there were more cardiovascular protective factors in T2DM patients with osteoporosis, the risk of all-cause mortality and CVD mortality remained high.

In recent years, there has been a rapid rise in the occurrence of osteoporosis as a result of T2DM. However, the correlation between BMD or osteoporosis and the likelihood of all-cause mortality and CVD mortality has not been extensively researched in this specific population group. Specifically, there were no conclusive findings regarding the associations with the risk of mortality from CVD. Our research validated a notable inverse relationship between BMD and the likelihood of death from any cause and CVD in individuals with T2DM, with both osteoporosis and osteopenia independently linked to higher risks of all-cause mortality and CVD mortality. These findings expanded the range of potential applications of the previous results and confirmed that osteoporosis was a separate indicator of CVD mortality.

This study also has some limitations. First, the cross-sectional nature of this study made it impossible to measure changes in BMD over time, so we could not determine whether their changes were related to these associations, so that the evaluation of causality in osteoporosis and T2DM was also limited. Second, most of the studies examining the association between bone health and cardiovascular health had used postmenopausal female populations who had a relatively higher risk for both osteoporosis and CVDs when compared with premenopausal women [13, 14]. Although this study performed a weighted analysis, the sample size was relatively small, and the number of postmenopausal women with T2DM and osteoporosis was very small, so we did not conduct further sensitivity analysis on this population. Therefore, further prospective studies with larger sample sizes are required. Third, some data on variables was obtained through self-reported questionnaires, which might introduce recollection bias and under-represent the real situation. In addition, we also may not have accounted for all potential confounders, even after controlling for recognized risk factors for mortality.

In conclusion, our findings indicated that osteoporosis and osteopenia were independently linked with an elevated risk of all-cause and CVD mortality among US individuals with T2DM at multifactor-adjusted long-term follow-up. These associations were stronger in participants with larger waists and higher total TG levels. As a result, the clinical diagnosis of osteopenia or osteoporosis in adults with T2DM provided independent prognostic value for CVD and all-cause mortality. Future research should explore the potential mechanisms of this association and examine whether therapies aimed at improving BMD can reduce the incidence of CVD events in this population.

BMD, bone mineral density; T2DM, type 2 Diabetes Mellitus; CVD, cardiovascular disease; NHANES, National Health and Nutrition Examination Survey; BMI, body mass index; HDL-C, high density lipoprotein cholesterol; TC, total cholesterol; TG, total triglyceride; Cre, creatinine; BUN, blood urea nitrogen; UA, uric acid; HbA1c, hemoglobin A1c; DXA, dual-energy X-ray absorptiometry; QUS, quantitative ultrasound; BUA, broadband ultrasound attenuation; AGES, advanced glycation end products; RCS, restricted cubic spline; HR, hazard ratio; CI, confidence interval.

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

HPL and BLW conceived the study and wrote the original manuscript. DSX, JLZ and CHW provided help and advice on images, tables and manuscript development. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The National Health and Nutrition Examination Survey (NHANES) is conducted by the U.S. National Center for Health Statistics (NCHS), part of the Centers for Disease Control and Prevention (CDC). The survey protocols were approved by the NCHS Research Ethics Review Board (Protocol #2005–06, Continuation of Protocol #2005–06, and Continuation of Protocol #2011–17), and all participants provided written informed consent. The study was conducted in accordance with the guidelines of the Declaration of Helsinki. Since NHANES data are publicly available and de-identified, no additional institutional review board approval was required. Detailed information on NHANES procedures and ethical guidelines is available on the official NHANES website.

This study was financially supported by the fund from the Natural Science Foundation of the University of Anhui Province to Changhui Wang [Grant Number: KJ2019A0265], and the Grant from Anhui Medical University [Grant Number:2020xkj158].

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/j.rcm2512434.