Interplay between orthopedic interventions and dementia: Dementia risk after total knee replacement

Dear Editor,

The interplay between orthopedic events and dementia is complicated. A recent Japanese study by Matsumoto et al. revealed that individuals with early‐onset dementia faced an increased likelihood of experiencing osteoporotic fractures compared to those without cognitive impairments. ¹ As for the reverse direction of orthopedic events–dementia association, integrated evidence showed that osteoarthritis patients were at higher risk of developing dementia and cognitive impairments. ² However, whether orthopedic surgical interventions, such as joint arthroplasty, influence the onset of dementia remains controversial. Cognitive dysfunction among individuals who underwent total joint arthroplasty was evaluated in recent studies. ³ , ⁴ A US study reported that individuals who had undergone total joint replacement demonstrate no significant disparity in the degree of cognitive decline compared to controls. ⁴ Nonetheless, the existing body of literature predominantly comprises small‐scale investigations; large‐scale real‐world studies investigating whether patients undergoing joint replacement surgery are susceptible to dementia based on the US population are lacking. Therefore, we performed an analysis in the TriNetX research network to evaluate the risk of new‐onset dementia following total knee replacement (TKR) surgery among patients with osteoarthritis.

We utilized subsets of the TriNetX network, including the US collaborative network, the Global Collaborative Network, and the EMEA collaborative network. The US network comprises 64 institutions in the United States, covering data from over 18 million patients, and has been widely utilized in epidemiological studies. ⁵ , ⁶ The Global network includes 119 institutions across 19 countries, with data from over 120 million patients. The EMEA network consists of 25 institutions across nine European countries, with data from over 14 million patients. The TriNetX database undergoes monthly updates, ensuring up‐to‐date information. Participants diagnosed with osteoarthritis between January 1, 2005, and December 31, 2018, with more than two visit records were included. The TKR group comprised osteoarthritis patients with a TKR record. Propensity score matching in a 1:1 ratio (adjusted for covariates such as age, sex, race, socioeconomic status, comorbidities, medications, laboratory data, medical utilization status, and substance use) was done to determine controls. Exclusion criteria included individuals under 18, those with a history of neurocognitive disorders or neoplasms, and individuals deceased before or after the index date. The primary outcome was incident dementia, with participants followed from 3 months after the index date until dementia occurrence, last visit, or December 31, 2023, whichever came first. After matching, there were 38,358 TKR patients and the same number of non‐TKR controls included for further analysis. All sensitivity analyses and stratification analyses were performed based on the US collaborative network. Given the significant influence of age and sex on dementia risk, we conducted stratification analyses based on these factors. Age subgroups included 18 to 64 years, 65 to 79 years, and over 80 years. Also, to enhance internal validity, sensitivity analyses were conducted using different approaches: (1) Varying wash‐out periods: To mitigate the impact of reversed causation, we applied wash‐out periods of 12, 24, and 36 months. Incidents within these periods were excluded. (2) Varying follow‐up periods: As the main analysis had a 5‐year follow‐up, we examined shorter durations of 1 and 3 years after the index date to assess their effect on incident dementia. (3) Employing different matching algorithms: To counter potential overmatching bias, we explored models without propensity score matching and those with fewer covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models via the TriNetX analytical platform. Ethical approval was exempted by the Institutional Review Board (IRB) of Tungs’ Taichung MetroHarbor Hospital (IRB TTMHH No.: 112208N). In the US population, TKR was associated with a 26% reduced risk of dementia (HR = 0.740; 95% CI: 0.647 to 0.846). This trend persisted across sensitivity analyses using different datasets, wash‐out periods, and matching algorithms. Stratification by gender showed a 35.2% and 29.5% risk reduction in male and female TKR patients, respectively. Among patients over 80, a 30% reduction in dementia risk was observed (HR = 0.697; 95% CI: 0.596 to 0.814). In 1‐ and 3‐year follow‐ups, HRs were 0.473 (95% CI: 0.326 to 0.685) and 0.541 (95% CI: 0.448 to 0.654), respectively (Figure 1).

FIGURE 1.

Risk of dementia after total knee replacement. Matching Model 1: Matching covariates include age, sex, and race. Matching Model 2: Matching covariates include age, sex, race, medical utilization, and comorbidities. In the TriNetX Analytics system, if the number of patients was ≤10 in any circumstances, the result of the count would be presented as 10 for deidentification purposes. In the 18 to 64 age subgroup, the precise number of incident cases was too small and unpresentable in the TriNetX Analytics system. Propensity score matching was reperformed in each analysis. TKR, total knee replacement; CI, confidence interval; NA, not available.

The results indicate a possible protective influence of TKR against dementia onset in osteoarthritis patients. Teipel et al. reported a decrease in dementia risk when follow‐up began four quarters after joint replacement surgery. ⁷ In our report, despite the limitation of residual confounders, the significance of reduced dementia risk persisted across different follow‐up periods. Possible mechanisms for this relationship include TKR's pain relief and improved mobility, which could lead to increased physical activity and social interaction, known to reduce dementia risk. ⁸ , ⁹ However, further research is needed to confirm these mechanisms.

AUTHOR CONTRIBUTIONS

All the authors were involved in drafting or revising the article and approved of the submitted version. Study conception and design: Hui‐Chin Chang, Chih‐Lung Wu, Wen‐Chieh Liao, Ru‐Yin Tsai, Chen‐Pi Li, Shiu‐Jau Chen, and Shuo‐Yan Gau. Data acquisition: Hui‐Chin Chang and Shuo‐Yan Gau. Data analysis and demonstration: Hui‐Chin Chang, Shiu‐Jau Chen, and Shuo‐Yan Gau. Original draft preparation: Hui‐Chin Chang, Chih‐Lung Wu, Wen‐Chieh Liao, Ru‐Yin Tsai, Chen‐Pi Li, Shiu‐Jau Chen, and Shuo‐Yan Gau.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.

ETHICS STATEMENT

This study was approved by the Institutional Review Board (IRB) of Tungs’ Taichung MetroHarbor Hospital (IRB TTMHH No.: 112208N). Informed consent was exempted by the IRB.

Supporting information

Supporting Information

DATA AVAILABILITY STATEMENT

Data in this study were retrieved from TriNetX Research Network. All data available in the database were administrated by the TriNetX platform. Detailed information can be retrieved at the official website of the research network (https://trinetx.com).