Using NHANES 2005–2010 and 2013–2014 data, we demonstrated that increased bone mineral density was significantly positively related to decreased mortality from all causes and cardiovascular diseases among US adults with T2DM.Meanwhile,we found that, after multivariate adjustment, osteoporosis and osteopenia were independently associated with an increased risk of all-cause and CVD mortality in T2DM patients at long-term follow-up.In terms of CVD mortality,stratified analyses suggested that these associations were stronger in participants who had a wider waist and higher total triglyceride,and the relationships in other stratified were mostly consistent with the total T2DM patients.In addition,a variety of sensitivity analyses indicated the robustness of our findings.
Some previous studies had reported a correlation between BMD or osteoporosis and the risk of all-cause mortality and CVD mortality.Research by Cai S showed that total femur (HR = 1.36, 95% CI = 1.07–1.73), femur neck (HR = 1.41, 95% CI = 1.11–1.78), intertrochanter (HR = 1.34, 95% CI = 1.05–1.72), and entire body (HR = 1.36, 95% CI = 1.09–1.69) osteoporotic participants had a higher risk of all-cause mortality compared with normal participants.However,the statistically significant L-shaped relationships were only identified for heart disease mortality with BMD increment within certain limits in the femur, whereas the remarkable relationships disappeared after BMD continued to increase[14].Other findings from nationally representative cohorts also suggested that osteoporosis was associated with an increased risk of all-cause mortality(HR = 1.37, 95% CI = 1.11, 1.68), and this association was stronger in participants who were older and had a lower BMI.Similarly, non-significant results were observed for osteoporosis with CVD mortality in their study, the non-significant results might be due to the lower number of incident CVD, and cancer deaths, and short-time follow-up[15].Other studies had drawn some positive conclusions on the relationship between osteoporosis and cardiovascular disease risk.Irene's study included a total of 305,072 UK Biobank participants diagnosed with osteoporosis at baseline, the study concluded 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[16].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, A. K. Gebre found that quantitative ultrasound measurements of the calcaneus were independently associated with increased cardiovascular and all-cause mortality, independent of established cardiovascular risk factors.Reduction in broadband ultrasound attenuation (BUA) in the minimally and multi-variable adjusted model including cardiovascular risk factors increased 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 geriatric females only, and the results were not founded on the analysis of BMD values [17].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, but regrettably, this study also showed that lower vBMD was not linked to other mortality risk factors, including subclinical atherosclerosis[18].
It was worth noting that in the process of sensitivity analysis, when we only retained T2DM patients without previous history of acute CVD, such as heart failure, angina pectoris, coronary heart disease, myocardial infarction, stroke ,and so on, the increased risk of CVD mortality in T2DM patients with reduced bone mass was not significant compared with normal bone mass patients, but the increased risk of CVD mortality in T2DM patients with osteoporosis was still steady. This suggested that the increased risk of mortality directly caused by emerging CVD was significant only when bone mineral content was extremely deficient, and further confirmed that osteoporosis was closely related to both the incidence of CVD and the increased risk of CVD mortality.
Impaired bone quality of osteoporosis and increased fracture risk had become recognized complications of diabetes mellitus[19].The pathophysiological mechanism of osteoporosis caused by T2DM was multifactorial, involving relatively reduced bone formation, osteoblast dysfunction, and low bone turnover[20].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[21–24].Degraded bone quality and microarchitectural defects are the result of multiple factors, including chronic hyperglycemia and skeletal advanced glycation end products (AGES), which irreversibly accumulated from the nonenzymatic addition of sugar moieties to the amine groups of proteins. AGES negatively impacted skeletal integrity, particularly type 1 collagen [25–30].T2DM and osteoporosis were two extremely common adverse conditions of cardiovascular disease, and they three shared several risk factors involved in their pathophysiological mechanisms, including aging, smoking, weight gain, inactivity, estrogen deficiency, hyperlipidemia, oxidative stress, chronic inflammation and common polygenes[31–35].Therefore, an increase in bone loss in this particular T2DM population was still strongly associated with an increase in the risk of cardiovascular and all-cause mortality.
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 total triglyceride levels, possibly because of the wide waist and high total triglyceride levels were themselves independent risk factors for adverse cardiovascular outcomes in T2DM.It was worth noting that our results showed that patients with osteopenia and osteoporosis had lower BMI, lower TC, TG levels, and higher HDL-C levels. Yang's research revealed a positive correlation between BMI and the BMD of the lumbar vertebrae and femoral neck[36]. Zhao's study reached the same conclusion, and they also believed that the level of HDL-C was positively correlated with BMD, and that elevated HDL-C had a protective effect on osteoporosis (OR = 0.07,95%CI0.01,0.53,p < 0.05)[37]. This was consistent with our findings.The relationship between the levels of TC,TG and osteoporosis was still controversial. In previous studies, Low BMD usually promoted atherosclerotic lipid abnormalities[38],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[39]. However, What's puzzling was that the above factors were generally considered to be protective factors for cardiovascular disease, which was exactly the opposite of our findings.To explain this phenomenon,we believed that diabetes-induced osteoporosis represented 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[40, 41].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.
Study strengths and limitations
The incidence of osteoporosis secondary to T2DM had increased rapidly in recent years, but in this particular population, the relationship between BMD or osteoporosis and the risk of all-cause mortality and CVD mortality had rarely been studied in detail.In particular, no definitive conclusions had been reached regarding the affiliations with the risk of CVD mortality.Our study confirmed a significant negative correlation between BMD and the risk of all-cause mortality and CVD mortality in patients with T2DM,while osteoporosis and osteopenia were independently associated with increased risk of all-cause mortality and CVD mortality. This result further extended the scope of application of the previous conclusions and clarifies that osteoporosis was an independent predictor of CVD mortality.
This study also had some limitations. First, The cross-sectional nature of this study made it impossible to draw any conclusions about the cause and effect of osteoporosis and type 2 diabetes. 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 cardiovascular diseases when compared with premenopausal women.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 were required.Third, some data on variables was gleaned 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.