We are the first group to show that osteoporosis of the femoral neck is an independent predictor of cognitive impairment in the acute phase and recovery phase of ischemic stroke. Additionally, osteoporosis of the femoral neck increases the risk of either moderate or severe WMD. These results have significant clinical implications. Despite recommendations to measure BMD in patients with acute stroke presenting risk factors for osteoporosis, BMD is not evaluated routinely in most stroke centers [18, 19]. Approximately 40% of patients with hip fracture have a cognitive impairment [20]. Because stroke could lead to an increased risk of cognitive impairment, the early detection and treatment of osteoporosis might promote improved cognitive function in patients with stroke.
In the present study, the percentages of patients presenting a cognitive impairment based on a K-MMSE score <24 score were 63.8% (28.8% with a mild cognitive impairment and 35.0% with a severe cognitive impairment) during the acute phase and 63.6% (30.1% with a mild cognitive impairment and 33.5% with a severe cognitive impairment) during the recovery phase of ischemic stroke. Although the pre-stroke cognitive status was not available in the present study, the proportion of patients presenting with a cognitive impairment during the recovery phase of stroke is comparable to previous studies reporting a prevalence of cognitive impairment after stroke ranging from 24% to 70% [21]. Regarding the prevalence of post-stroke cognitive impairment, findings from this study support emerging evidence of the importance of improving strategies designed for the secondary prevention of post-stroke cognitive impairment. In addition, the associations between osteoporosis and MoCA scores in the sensitivity analysis support our main findings. Based on our results, we cautiously recommend that clinicians use the BMD as a new marker of cognitive impairment after stroke.
Our study revealed the association between osteoporosis and cognitive impairment but did not demonstrate causality. Osteoporosis is known to affect microvascular diseases, such as cerebral WMD. The same mechanisms of dysregulated proteolytic processing and ion and electron transport have been described in genetic and laboratory studies of both cerebral WMD and bone osteoporosis [22, 23]. In addition, WMD is a strong predictor of vascular cognitive impairment and dementia [24-27]. Notably, the mediator effect analysis showed that WMD was potentially attributed to the BMD and cognitive impairment during the recovery phase of acute ischemic stroke. Based on these laboratory and statistically results, we carefully postulated that osteoporosis affects cognitive function by inducing microvascular damage during WMD progression. However, we should be cautious when generalizing this finding, since we did not consider unmeasured confounding factors.
Interestingly, femoral neck BMD, but not lumbar spine BMD, was associated with severity of cognitive impairment and WMD. In previous studies of cardiovascular disease, femoral neck BMD was significantly associated with severe coronary atherosclerosis and an increased risk of coronary artery disease [28, 29]. This association was explained by the greater likelihood that spinal BMD will be affected by drugs, medical conditions and degenerative arthritis in elderly people than femoral neck BMD [30]. The correlation between the volumetric femoral neck and lumbar spine BMDs and the MMSE score and the association between the femoral neck BMD and MoCA score in this study strongly support this hypothesis. Therefore, femoral neck BMD potentially represents a more useful marker for predicting cognition and WMD than lumbar spine BMD. However, since both femoral neck and lumbar spine BMD were associated with a poor outcome in a previous analysis of cerebrovascular disorders [2], and other studies measured only the femur neck BMD to investigate stroke risk [1, 3], we should use caution when generalizing these results. Nonetheless, these results could prompt researchers to identify a reasonable BMD site for predicting cognition in patients with stroke. Further studies are needed to clarify this issue.
Osteoporosis is associated with atherosclerosis [31-34], but this association remains controversial [35]. Most of these studies have focused on coronary artery disease. In the study, large artery atherosclerosis tended to be an uncommon ischemic stroke mechanism, whereas the incidence of stroke caused by small vessel occlusion tended to be high in patients with osteoporosis. Although osteoporosis is known to share risk factors with atherosclerosis, studies examining the relationship between atherosclerosis and osteoporosis in patients with ischemic stroke are rare. Regarding the ischemic stroke mechanism, the proportion of patients presenting with atherosclerosis who are diagnosed with ischemic stroke is relatively low (ranging from 9.3% to 20.9% in patients with ischemic stroke) than the proportion of patients presenting with atherosclerosis who are diagnosed with coronary artery disease [10]. Thus, osteoporosis may exhibit a stronger correlation with microvascular disease than with atherosclerosis in subjects with a brain infarction. However, this conclusion should be interpreted with caution due to the small sample size of our study.
Although this study is the first to show an association between a low BMD and cognition in patients with stroke, it has several limitations. First, this study was a single-center study with a relatively small number of subjects, despite the use of a prospective database. Further multicenter studies assessing cognitive function should be established to confirm our results. Second, since this study employed a cross-sectional design, we were unable to determine causality between cognition and BMD. The levels of vitamin D and osteocalcin, potential mediators of the observed associations, were not available for all subjects. However, we proposed that WMD had an important role in the effect of BMD on cognitive decline. These findings might allow clinicians to establish a clinical strategy that predicts cognitive impairment after stroke. Third, in the present study, the mean age of all subjects was high (72.9±10.5 years), and the osteoporosis group tended to be older than the non-osteoporosis group, which may have affected the outcome. Post-stroke depression also could affect the cognition of the subjects. After reviewing the Geriatric Depression Scale (GDS), which was administered at the same time as the MMSE, the GDS scores were not different between the two groups (data were not shown). Since we adjusted for age in all multivariate models and found no difference in GDS scores between the osteoporosis group and the non-osteoporosis group, we assume that the impacts of age and depression on the outcomes have been attenuated in this study. Fourth, although we controlled for known measurable confounders in the multivariate analysis, unmeasured confounding factors (physical activity and gait speed prior to stroke, acute stressors such as emotional stress and depression due to hospitalization or stroke symptoms, etc.) could remain and may threaten the generalizability of our results. Although scores for physical activity and gait speed prior to stroke were not available in this study, we excluded subjects with independent functional statuses (mRS >3), and the 3-month functional status scores (mRS >2) were not different between the two groups. In addition, acute stressful situations can affect the cognitive status of a patient in the acute phase of stroke. However, we aimed to evaluate the impact of osteoporosis on cognition 1 year after stroke onset, which should therefore be free from confounding by the effects of acute stressful situations. We additionally found that the adjusted ORs for the effect of osteoporosis on cognition tended to increase in the recovery phase (Table 2). Fifth, the effects of the stroke itself (lesion locations and infarct volume, etc.) on delayed cognitive impairment were not considered in the present study. However, the locations of stroke lesions were not significantly different between the osteoporosis group and non-osteoporosis group. Although the infarct volume was not available in our study, we cautiously suggest that a lack of difference in the proportions of lesion locations could increase the validity of our results. Last, since the cognitive function test was not administered prior to stroke, the patients’ pre-stroke cognitive statuses were unavailable. However, the aim of our study was to determine the trend in cognitive decline during the acute and recovery phases in both the osteoporosis and non-osteoporosis groups and to compare the impact of osteoporosis on cognitive function in those two phases of stroke. Since we compared the effect of BMD on cognitive impairment in both the acute and recovery phases of stroke, our results could have important clinical implications.