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SEX DIFFERENCE IN THE ASSOCIATION BETWEEN PRIOR FRACTURE AND SUBSEQUENT RISK OF INCIDENT DEMENTIA: A LONGITUDINAL COHORT STUDY

 

D. Gao1,2, W. Rong3, C. Li1,2, J. Liang4, Y. Wang1,2, Y. Pan4, W. Zhang4, F. Zheng4, W. Xie1,2

 

1. Heart and Vascular Health Research Center, Peking University Clinical Research Institute, Peking University First Hospital, Beijing, China; 2. Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China; 3. Department of Orthopedics, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University, Beijing, China; 4. School of Nursing, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Corresponding Author: Fanfan Zheng, School of Nursing, Peking Union Medical College, Chinese Academy of Medical Sciences, 33 Ba Da Chu Road, Shijingshan District, 100144, Beijing, China; E-mail: zhengfanfan@nursing.pumc.edu.cn; Wuxiang Xie, Peking University Clinical Research Institute, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, 100034, Beijing, China; E-mail: xiewuxiang@hsc.pku.edu.cn

J Prev Alz Dis 2024;
Published online March 13, 2024, http://dx.doi.org/10.14283/jpad.2024.56

 


Abstract

BACKGROUND: A history of fracture has been associated with increased risk of dementia; however, it is uncertain whether sex difference exists in the association between prior fracture and subsequent risk of incident dementia.
OBJECTIVES: To investigate whether sex modified the relationship between prior fracture and subsequent risk of dementia.
DESIGN: Prospective cohort study.
SETTING: UK Biobank.
PARTICIPANTS: 496,331 participants (54.6% women) free of dementia at baseline.
MEASUREMENTS: History of fracture was self-reported via touchscreen questionnaires at baseline. The primary outcome was all-cause dementia.
RESULTS: Both any fracture and fragility fracture were significantly associated with an increased risk of subsequent all-cause dementia in men (adjusted hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.14-1.43; adjusted HR: 1.48; 95% CI: 1.18-1.87, respectively), but not in women (adjusted HR: 1.04; 95% CI 0.95-1.15; adjusted HR: 1.01; 95% CI: 0.87-1.18, respectively); and these sex-differences were significant (P interaction = 0.006; P interaction = 0.007, respectively). The sex differences in the impacts of different fracture sites (including upper limb, lower limb, spine, and multiple sites) were consistent on all-cause dementia.
CONCLUSIONS: This study demonstrated that prior fracture was associated with an increased risk of dementia in men but not in women, and the sex difference was significant. Previous fracture may be an important marker for identifying subsequent dementia in middle-aged and older men.

Key words: Sex difference, fracture, dementia, prospective cohort.


 

Introduction

Dementia is a fast-growing global epidemic that affects memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgment (1). Approximately 57.4 million individuals worldwide suffered from dementia and there were more women with dementia than men (female-to-male ratio of 1.69) in 2019 (2). Driven by the sharp increase in population aging, dementia poses enormous pressure on healthcare and fiscal systems. Similar to dementia, fracture is also related to the huge burden of the public health system, which gradually increases with the raising number of older people (3, 4). In 2019, the age-standardized prevalence rate of fracture was 5614.3 per 100,000 population, and sex difference was found in the age-standardized rates of prevalent fracture that the age-standardized prevalence in males was higher than that in females (5).
Recently, five observational studies (four cohort studies (6-9) and one case-control study (10)) have investigated the association between fracture and risk of dementia and draw a relatively consistent conclusion that people with prior fracture had a higher risk of dementia. Among them, three studies investigated the association between a fracture in a certain area, including facial, hip, distal radius or spine fracture with dementia (6, 9, 10). The remaining two studies explored the association between any fracture and dementia (7, 8). However, sex differences in the association between fracture and subsequent risk of dementia have been briefly discussed in only three studies (7, 8, 10) and no consistent conclusion has been reached. Besides, these three studies were all retrospective and conducted in East Asian populations using data from health insurance claims databases or electronic medical database. Studies exploring sex difference in the association between fractures and dementia based on prospective design are scarce.
Providing that sex is an important modifier for many diseases including dementia and fracture, it is valuable to examine the sex differences in the association between previous fracture and the risk of subsequent dementia in populations from different regions. This information could aid in identifying specific issues concerning the prognosis of sex-specific fracture patients and the prevention of dementia. Herein, by using data from the UK Biobank, the present prospective cohort study aimed to investigate the association between prior fracture and subsequent risk of incident dementia in both women and men, and further explore whether sex difference exists in this association.

 

Materials and Methods

Data sources and participants

The UK Biobank is a large prospective cohort study of over 500,000 participants aged between 40 and 69 years when recruited in 2006-2010 (11). Participants included attended assessment visit comprised electronic signed consent, self-completed touch-screen questionnaires, brief computer-assisted interview, physical and functional measures, and provided biological samples in 22 assessment centers throughout the United Kingdom (12). Ethics Committee approval for UK Biobank was obtained from the North West Multi-Centre Research Ethics Committee (Research Ethics Committee reference: 16/NW/0274).(11)
In this analysis of the UK Biobank study, we extracted baseline data and follow-up information on incident dementia via linked electronic health records (13). Participants were excluded from the study if they had a confirmed diagnosis of dementia (n = 228) or with missing fracture evaluation data (n = 933) at the baseline assessment. To avoid a possible reverse causality, participants were also excluded if they developed dementia within the first 3 years of follow-up (n = 272) or had a follow-up period less than or equal to 3 years (n = 4,647) (14, 15). After these exclusions, altogether 496,331 participants were included in this study. Details of participants selection procedures are presented in Figure 1.

Figure 1. Participants Selection Diagram

 

Primary exposure

History of fracture was self-reported via touchscreen questionnaires at baseline. All participants were asked if they had fractured/broken any bones in the last 5 years. If yes, two further questions would be requested to answer. One was whether the fracture resulted from a simple fall. Another question asked about specific fracture sites (ankle, leg, hip, spine, wrist, arm, other bones), which was a multiple-choice question. According to the answers to these three questions, the main exposure indicators were defined. Only those participants who had clearly reported their previous fracture history would be defined as having a history of any fracture. Fragility fracture was defined as a low-trauma (occurring as a result of a fall) fracture involving the hip, spine, wrist, or arm (16). The specific fracture site was directly defined according to the participants’ options. And if participants reported two or more fracture sites, a new variable “Multiple sites” would be generated.

Primary outcomes

Incident all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VD) were ascertained using diagnoses obtained from the Hospital Episode Statistics for England and Patient Episode Database for Wales and death register data from NHS Digital. Individuals with dementia were identified using International Classification of Diseases (ICD)-10 codes specified by the UK Biobank all-cause dementia, AD and VD algorithm (Supplemental Table S1). All outcomes were followed up to December 31, 2021.

Covariates

Sex information was derived from NHS and/or touchscreen questionnaire. Information on ethnic background, education, current smoking, alcohol intake, physical activity and depressed mood was collected from the touchscreen questionnaire. Obesity was defined according to whether body mass index (BMI, kg/m2) was greater than or equal to 30. Weight and height were measured during the physical examination. Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg, self-reported hypertension or anti-hypertensive medication use. Diabetes was defined as glycated hemoglobin≥6.5%, self-reported history of diabetes, or medication use for lowering blood glucose. Information on stroke and coronary heart disease was collected from both touchscreen questionnaires and verbal interviews. The APOE ε4 carrier status was defined by genetic information from the UK Biobank. For more details on covariates collection and definitions see Supplemental Table S2. History of osteoporosis at baseline was defined as M80 (osteoporosis with pathological fracture), M81 (osteoporosis without pathological fracture) or M82 (osteoporosis in diseases classified elsewhere) using the ICD-10 code (17). According to previous studies (18-20), frailty status was assessed using five frailty phenotype indicators including unintentional weight loss, exhaustion, weakness, slow gai speed, and low physical activity. The detailed definitions of the 5 indicators were presented in the Supplemental Table S3. Participants were categorized into non-frail (frailty phenotype score=0), pre-frail (frailty phenotype score≥1 and ≤2), and frail (frailty phenotype score≥3).

Statistical analysis

Baseline characteristics were analyzed in men and women separately, reporting mean (standard deviation [SD]) or median (interquartile range [IQR]) for continuous variables and number (percentage [%]) for categorical variables. Baseline characteristic differences between sexes were tested by using t test in case of the normality distribution or Mann-Whitney U test in case of the non-normality distribution for continuous variables and chi-square test for categorical variables, respectively.
Cox proportional hazards models with age at onset as the time scale were developed to explored associations between previous fracture, fragility fracture, specific fracture sites with the risk of developing dementia, with results expressed as hazard ratio (HR) and 95% confidence interval (95% CI) (21). The Cox models were adjusted for baseline ethnic background, education, current smoking, alcohol intake, physical activity, depressed mood, obesity, hypertension, diabetes, coronary heart disease, stroke, and APOE ε4 carrier status. We used the Z-test proposed by Altman and Bland to evaluate the sex differences in regression coefficients estimated from Cox models (22).
To test the robustness of major findings, we performed sensitive analyses as follows. (1) As death is a competing risk for dementia, the competing risk regression models, with death as the competing event of dementia, was used to compute the sub-hazard ratios (SHRs) measuring the association between previous any fracture, fragility fracture with all-cause dementia. (2) We excluded everyone diagnosed with stroke at baseline. (3) We excluded participants who developed dementia within five years after baseline or had a follow-up period less than or equal to 5 years to further control possible reverse causality. (4) We excluded participants aged less than 60 years old at baseline, as the risk of incident dementia of these participants was relatively low. (5) Given the unprecedented impact by the COVID-19 pandemic on health-care systems, we restricted our follow-up to the pre-pandemic by December 31, 2019.
Analyses were performed using SAS version 9.4 (SAS Institute) and R version 4.1.2 (R Foundation for Statistical Computing). Statistical significance was defined as P-value < 0.05; all tests were 2-tailed.

 

Results

Baseline characteristics

270,837 women and 225,494 men were included in the analyses. Table 1 presents baseline characteristics of individuals by sex. A total of 46,842 (9.4%) participants reported previous fracture in the past 5 years: 27,617 (10.2%) in women and 19,225 (8.5%) in men. Besides, the details of baseline characteristics of the participants stratified by sex and fracture status were presented in Supplemental Table S4.
Frailty status of participants was descripted in Supplemental Table S5. Both male and female participants with a history of fracture were more likely to be frail. Among males with a history of osteoporosis, 44.3% were pre-frail and 10.5% were frail, while among females with a history of osteoporosis, 42.6% were pre-frail and 8.4% were frail.

Table 1. Baseline Characteristics of Study Participants by Sex

* P-Value reported for differences between sexes using t test in case of normality, Mann-Whitney U test in case of non-normality of the distribution, chi-square test for categorical variables

 

Association between fracture and incident dementia

Table 2 shows results for the association of previous any fracture/fragility fracture and subsequent risk of all-cause dementia, AD and VD. 3,505 women and 3,864 men developed all-cause dementia during the follow-up period (median: 12.9 years). In women, neither previous any fracture nor fragility fracture were associated with the subsequent all-cause dementia (adjusted HR, 1.04; 95% CI, 0.95-1.15; P-value = 0.389; adjusted HR, 1.01; 95% CI, 0.87-1.18; P-value = 0.899, respectively). Compared to men without any previous fracture, men with any previous fracture showed a 28% increased risk of all-cause dementia (adjusted HR, 1.28; 95% CI, 1.14-1.43; P-value < 0.001). Compared to men without prior fragility fracture, men with prior fragility fracture showed a 42% increased risk of all-cause dementia (adjusted HR, 1.48; 95% CI, 1.18-1.87; P-value < 0.001). Tests for interaction demonstrated that sex significantly modified the relationships of any fracture and fragility fracture with subsequent risk of all-cause dementia (all P-value for interaction < 0.05). The sex differences in associations of fracture with incident AD and VD were similar.

Table 2. Prior Fracture Situation in the Past 5 Years of Women and Men and the Risk of Dementia Incidence

* Adjusting for baseline ethnic background, education, current smoking, alcohol intake, physical activity, depressed mood, obesity, hypertension, diabetes, coronary heart disease, stroke, and APOE ε4 carrier status.

 

Associations between site-specific fracture and incident dementia

As shown in Figure 2, the sex differences were still observed in the associations between different fracture sites and incident dementia. Significant interactions were observed between upper limb fracture, lower limb fracture or multiple sites fracture and sex in predicting all-cause dementia (all P-value for interaction < 0.05). However, due to insufficient AD and VD events when analyzing the relationships between site-specific fractures and subtypes of dementia, significant modifying effects of sex were only observed on the associations of upper limb fracture and spine fracture with AD (Supplemental Figures S1 and S2).

Figure 2. Prior Fracture Site in the Past 5 Years of Women and Men and the Risk of All-cause Dementia Incidence

Abbreviations: HR, hazard ratio; CI, confidence interval. * Adjusting for baseline ethnic background, education, current smoking, alcohol intake, physical activity, depressed mood, obesity, hypertension, diabetes, coronary heart disease, stroke, and APOE ε4 carrier status. † Pink squares represent hazard ratios for women, and blue squares represent hazard ratios for men. Horizontal lines indicate corresponding 95% confidence intervals around hazard ratios.

 

Sensitivity analysis

Results of competing risk regression models were presented in Figure 3. The accounting for mortality as a competing risk did not materially alter the associations between any fracture/fragility fracture and subsequent all-cause dementia in both men and women. And the P for interactions with sex were still significant (P-value for interaction = 0.048 for any fracture; P-value for interaction = 0.024 for fragility fracture). Similarly, the results were robust after excluding those who were diagnosed with stroke at baseline, developed dementia of lost follow up within five years after baseline, aged less than or equal to 60 years old at baseline, or further restricting to the pre-pandemic follow-up period (Supplemental Figures S3 to S6).

Figure 3. Association Between Any Fracture and Fragility Fracture with All-cause Dementia, Adjusting for the Competing Hazard of Death from Any Cause

Abbreviations: SHR, sub-distribution hazard ratio; CI, confidence interval. * Adjusting for baseline ethnic background, education, current smoking, alcohol intake, physical activity, depressed mood, obesity, hypertension, diabetes, coronary heart disease, stroke, and APOE ε4 carrier status. † Pink circles represent hazard ratios for women, and blue circles represent hazard ratios for men. Vertical lines indicate corresponding 95% confidence intervals around hazard ratios.

 

Discussion

In this large prospective cohort study of 496,331 participants from UK Biobank, we observed significant sex difference in the association between prior fracture and subsequent risk of incident dementia. Compared to male participants with no any fracture, men with a history of any fracture were significantly associated with a 1.28-, 1.29- and 1.55-fold higher risk of all-cause dementia, AD and VD. In female participants, however, the association between fractures and dementia was not statistically significant.
The consideration of sex as a biological variable in medical research is crucial for enhancing our comprehension of the fundamental mechanisms contributing to disease risk and resilience (23). Sex-related biological factors modulate the risk for many diseases (23, 24). For example, women have a higher prevalence of osteoporosis, fractures (25), and dementia (2), which may be related to the effects of estrogen and gonadal hormones (23, 24, 26, 27). Evidence from a meta-analysis showed that fracture patients exhibited an increased risk of dementia with a pooled HR of 1.28 (28). However, previous evidence on sex difference in the association between fracture and incident dementia were scarce and inconsistent. A retrospective cohort study based on a claims database and a case-control study of participants aged≥60 years from a health insurance database, reported that the adjusted HRs/odds ratios for dementia of any fracture group, hip fracture group and spine fracture group in the male were higher than those in the female (8, 10). Another retrospective cohort study of 52,848 participants derived from electronic health records, however, came to the different conclusion that a significant association of hip fracture with an increased risk of dementia was observed in women (HR 1.15, 95% CI 1.08-1.22) but not in men (HR 0.95, 95% CI .86-1.05) over a follow-up period of about five years (6). The reasons for the inconsistency of sex differences between these studies with ours may be as follows: (1) different data sources; (2) different definitions of exposure factors; (3) different reference groups; (4) different follow-up duration. The current study adds to the literature by analyzing sex as a modifier of the association between fracture and dementia in a large prospective cohort, aiming to clarify the inconsistent results of the previous studies. The participants in this study were composed of community-dwelling individuals, providing a large sample size that allowed for the exploration of sex differences with sufficient power. Moreover, the data from the UK Biobank included information on the location of the fracture and whether the fracture was caused by a fall, allowing us to analyze the association between fracture and dementia more comprehensively. More importantly, the use of multisource prospectively collected data to ascertain incident dementia, including primary care, hospital inpatient, death registry records, and self-report, leading to a high positive predictive value of dementia (82.5%) (29).
To the best of our knowledge, this is the first prospective population-based cohort study comprehensively evaluating sex difference in the association between any fracture, fragility fracture and site-specific fracture, including upper limb, lower limb, and multiple sites, with all-cause dementia. The most important finding of this prospective study is that male fracture patients have a higher risk of subsequent dementia, which was not observed in female fracture patients. This finding represents an important contribution to recommendations for dementia prevention in people with fracture. For clinical implications, regular assessment of dementia risk is necessary for the health management of the older men who are diagnosed with fracture. Dementia is one of the most important causes of loss of functional independence in older individuals. Identifying those at risk as early as possible and initiating timely preventive measures such as preventing head injuries, maintaining physical activity, and reducing obesity to combat accumulated pathology are key to reducing the burden of dementia care (30, 31). For primary care, asking patients, especially males, a simple question about previous fracture could provide an easy, quick trigger for a more detailed dementia risk assessment. These simple questions about fracture may help distinguish high-risk populations among interventions aimed at maintaining or improving cognitive health in old age.
The mechanisms for the male-specific positive association between fracture and subsequent dementia are largely unknown, but there are several potential pathways for this association. First, fracture and dementia have many shared risk factors (32-41). These risk factors are not evenly distributed between men and women, which may lead to a higher risk of dementia in men with fractures. Second, the influence of onset age of fracture also needs to be considered. Although the UK Biobank did not contain the detailed time of fracture occurrence, our analysis found that men who reported fracture occurrence in the past five years were younger than women, which suggested that men who reported a history of fracture in this study may suffer fracture at a younger age. Several studies indicated that features of middle-aged fracture patients were male and high-energy trauma (5, 42, 43). Suffering heavier fracture at a younger age might have greater negative impacts on lifestyle and material situation, leading to a higher risk of dementia (44). The sex difference in osteoporosis screening is also an important factor to consider. Hormonal changes that occur after menopause significantly increase the risk of osteoporosis and fractures in women (45). In general, osteoporosis is considered to be a disease that mainly affects women (46). Previous studies also shown that male osteoporosis was underestimated, underdiagnosed, and undertreated (46). By the time a man is diagnosed with osteoporosis, he is more likely to be frail. In this study, we found that 54.8% of male patients with a history of osteoporosis were in a pre-frail or frail state, while the proportion was lower (51.0%) among female patients with a history of osteoporosis. Men diagnosed with fractures may have more severe conditions and be in a frail state, leading to a higher risk of dementia. There is a strong connection between physical impairment and cognitive decline. It is necessary to consider the possibility of dementia and physical impairment developing together. Since fractures, especially fragility fracture caused by a simple fall, could be due to impaired physical performance and frailty (47, 48). The relationship between fracture and dementia is a complex due to the potential bidirectionality of the association: fracture might be either the consequence of an ongoing neurodegenerative process, or events that independently hasten dementia progression (28, 49). Our study design did not allow us to determine a causal relationship between fracture and dementia, which is an important limitation of observational study design. However, our study excluded participants who developed dementia within the first 3 years of follow-up or had a follow-up period less than or equal to 3 years, which may reduce the possibility of reverse causality.
The sex difference in the association between fracture and subsequent dementia could be attributable to the protective effect of estrogen. Inflammatory response and reactive oxidative stress are viewed after fracture and during the healing process (50, 51). The injury caused by fracture initiates an inflammatory response which involves secretion of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, IL-11 and IL-8 (50, 52, 53). A significant association between the secretion of those inflammatory factors and risk of dementia has been investigated by several studies (54-56). Estrogen may exert protective effects against brain disorders through a variety of mechanisms, including anti-inflammatory, cholinergic neuroprotective and neurotrophic effects (57, 58). Furthermore, estrogen’s potential benefit for reducing the risk of dementia is suggested by epidemiologic observations of an inverse relationship between estrogen replacement therapy exposure and dementia diagnosis in women (59).
The strengths of our study include the prospective cohort design, long follow-up, large sample size and rich data resources. Several potential limitations should be carefully considered in present study. First, prior fracture was defined based on self-reported data, which may result in misclassification bias. Second, the possible existence of undiagnosed dementia cannot be entirely ruled out. Third, 6,080 participants were excluded, which might cause selection bias. Comparison of baseline characteristics between participants included (n=496,311) and excluded (n=6,080) demonstrated significant differences (Supplemental Table S6). In general, the participants included were younger and healthier, which may bias the associations observed in this study. Fourth, this is a relatively young cohort in terms of both fracture and dementia, which may limit the generalizability of the results to older, frailer populations. To address this limitation, we have performed sensitivity analyses among participants aged≥60 years and the results were consistent. Fifthly, since the current study population mainly consisted of the White ethnicity with a proportion of over 94%, which may not be representative of the general UK population, the generalization of the present findings should be cautious, and validation in other populations is warranted.

 

Conclusion

In conclusion, the findings of this study demonstrated that prior fracture is associated with an increased risk of dementia in men, but not in women. In male individuals, participants with prior any fracture, fragility fracture, upper limb fracture, lower limb fracture or multiple sites fracture had an increased risk of dementia incidence. Therefore, previous fracture may be an important marker for identifying subsequent dementia in middle-aged and older men. It is necessary to provide additional support for fracture patients, especially males, to manage or reduce the disease burden of fracture and subsequent dementia. Future studies are needed to explore the sex difference in pathophysiological mechanisms of fracture and subsequent dementia.

 

Ethical statement: Ethics Committee approval for UK Biobank was obtained from the North West Multi-Centre Research Ethics Committee (Research Ethics Committee reference: 16/NW/0274). As part of the UK Biobank recruitment process, informed consent was obtained from all individual participants included in this study.

Author contributions: Fanfan Zheng and Wuxiang Xie conceived the study. Darui Gao and Chenglong Li did the data analysis and data interpretation. Darui Gao drafted the initial manuscript. All authors critically revised the manuscript. Fanfan Zheng and Wuxiang Xie are the guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
Declaration of interests: All other authors declare that there are no competing interests.

Role of the funding sources: This study was supported by grants from the National Natural Science Foundation of China (project number 82373665 and 81974490), the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (2021-RC330-001), and the 2019 Irma and Paul Milstein Program for Senior Health Research Project Award. The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the manuscript; or the decision to submit the article for publication.

Data sharing: Data used in the present study were obtained from the UK Biobank under Application Number 90492. Further details can be found at https://www.ukbiobank.ac.uk.

Acknowledgements: We appreciate efforts made by the original data creators, depositors, copyright holders, the funders of the data collections, and their contributions to the access of data from the UK Biobank team (project no. 90492). We are also grateful to the participants for generously dedicating their time to take part in the UK Biobank study.

 

SUPPLEMENTARY MATERIAL

 

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