Malnutrition-Related Health Outcomes in Older Adults with Hip Fractures: A Systematic Review and Meta-Analysis

Hip fracture is a common condition in older adults, leading to disability and mortality. Several studies have demonstrated the association between nutritional status and the risk of a negative health outcome after fractures. In this systematic review, we evaluated the association between malnutrition and mortality, changes in mobility/living arrangements, and postoperative complications, such as delirium, in older patients with hip fractures. A literature search on the PubMed, Web of Science, and Scopus databases, up to September 2023, was conducted to identify all studies involving older subjects that reported an association between MNA/GNRI/PNI/CONUT and health outcome after hip fracture. Meta-analysis was performed by a random-effects model using risk values (RR, OR, and HR) extracted from the 14 eligible selected studies. Malnutrition significantly increased the risk of any analyzed adverse outcome by 70% at 1 month, and up to 250% at 1 year. Malnutrition significantly increased delirium risk by 275% (OR = 2.75; 95% CI 1.80–4.18; p ≤ 0.05), mortality risk by 342% (OR = 3.42; 95% CI 2.14–5.48; p ≤ 0.05), mortality hazard risk by 351% (HR = 3.51; 95% CI 1.63–7.55; p ≤ 0.05) at 1 month, and transfer-to-more-supported-living-arrangements risk by 218% (OR = 2.18; 95% CI 1.58–3.01; p ≤ 0.05), and declined mobility risk by 41% (OR = 1.41; 95% CI 1.14–1.75; p ≤ 0.05), mortality risk by 368% (OR = 3.68; 95% CI 3.00–4.52; p ≤ 0.05), and mortality hazard risk by 234% (HR = 2.34; 95% CI 1.91–2.87; p ≤ 0.05) at 1 year. Malnutrition of older patients increases the risk of death and worsens mobility and independence after hip fractures. The results of the present study highlight the importance of nutritional status evaluation of older subjects with hip fractures in order to prevent potential adverse outcomes (Registration No: CRD42023468751).


Introduction
Hip fractures in older people is a substantial concern to public health services and society [1,2].
In fact, this type of fracture, in the upper part of the femur, becomes more common with aging.This is because aging-related bone fragility is exacerbated by structural deterioration and bone loss.The combination of both skeletal fragility and a greater propensity to fall leads to a high occurrence of hip fractures with advancing age [1].
It was estimated that hip fracture affected 1.6 million persons globally in 2000, and by 2050, this number is expected to reach 6.3 million [3].
Hip fracture is associated with the development of negative consequences, such as disability, depression, cardiovascular diseases, and, consequently, mortality [2].Mortality within 1 year ranges from 20% to 40% in older patients [4,5].
Finding the risk factors for functional loss following hip fracture may help treat postoperative problems more effectively and lower the expenses of helping patients who become dependent on assistance due to institutionalization or loss of autonomy [6].
A recent systematic review found a range from 4% to 39.4% of hip fracture patients who were malnourished when they were admitted to hospital [7].
After a fracture, older patients who are undernourished may only partially regain their previous degree of independence in carrying out daily tasks and they have a reduced capacity to return to their pre-fracture functional status [8].
Malnutrition has been identified as a patient's poor nutritional status and as an important and modifiable prognostic factor for several medical conditions.
Due to its modifiability and the potential for early nutritional intervention to promote hip fracture recovery, malnutrition is a condition of great concern when combined with hip fracture [9].
Malnutrition can be detected by several validated tools (https://guidelines.espen.org/espen-web-app/home/, accessed on 26 September 2023).In particular, the following are the most used for older patients or surgical patients within the hospital setting: the Mini Nutritional Assessment Short Form (MNA-SF), the Mini Nutritional Assessment Long Form (MNA-LF), the Geriatric Nutritional Risk Index (GNRI), the Prognostic Nutritional Index (PNI), and the Controlling Nutritional Status (CONUT) score.
The MNA is a standardized and validated instrument to identify protein-energy malnutrition or the risk of malnutrition in older patients in various care settings and has already been proven as a useful diagnostic tool among older orthopedic patients [10,11].
The GNRI is a tool used for assessing the nutritional status of older individuals considering both body weight and serum albumin levels to evaluate the risk of malnutrition and associated complications in geriatric populations.The GNRI score ranges from 0 to 100, with higher scores indicating better nutritional status [12].
The PNI was developed to investigate the relationship between nutritional status and outcomes in surgical patients.It is based on serum albumin levels and total lymphocyte count.Lower PNI scores indicate poorer nutritional status, while higher scores suggest better nutritional status [13].
The CONUT score is used for nutritional assessment in clinical practice, in particular, for patients with various medical conditions.It considers three parameters: serum albumin levels, total lymphocyte count, and total cholesterol concentration.It was first proposed in 2005 as a means of evaluating the nutritional status and predicting outcomes in hospitalized patients [14].
Two-thirds of older patients are at a particular nutritional risk or are malnourished, with a wide impact on their overall health, physical functioning, and quality of life [15].
Poor nutritional status has been associated with several negative clinical outcomes, such as postoperative complications, pressure ulcers, functional dependence, walking impairment, impaired quality of life, and mortality [9,16].
A recent meta-analysis [17] examined association between nutritional indices and mortality after hip fracture, finding that patients with low GNRI or low MNA-SF scores had a significantly higher risk of mortality compared to those with higher scores, even though it was not assessed for different follow-up periods.
To the best of our knowledge, there are no systematic reviews and meta-analyses that investigate the association between malnutrition and health outcomes in consideration of different follow-up intervals from hip fracture; therefore, the aim of our systematic review is to evaluate the association between malnutrition and selected health outcomes in patients affected by hip fractures, in particular: mortality, mobility, changes in living arrangements, and postoperative complications.

Materials and Methods
The present meta-analysis was conducted following the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) guidelines [18] and PRISMA statement [19].
The protocol of this study has been recorded in the International Prospective Register of Systematic Reviews (www.crd.york.ac.uk/PROSPERO/ (accessed on 13 October 2023), Registration No: CRD42023468751).

Search Strategy and Data Source
We carried out a systematic literature search up to 26 September 2023 through the PubMed (http://www.ncbi.nlm.nih.gov/pubmed/),Web of Science (http://wokinfo.com/), and Scopus (https://www.scopus.com/)databases to identify original articles on the association between malnutrition and selected health outcomes in older individuals with hip fractures.
The The different associations of keywords combined with Boolean operators used for each database are shown in Supplementary Table S1.
No publication date limitation was applied but due to translation restrictions, only English-language studies were eligible.
We manually examined the reference lists of selected articles and recent relevant reviews to identify possible additional relevant publications.

Eligibility Criteria
Only the following tools were considered for inclusion: MNA-LF, MNA-SF, GNRI, PNI, and CONUT score.
Articles were included if they met the following criteria: (i) evaluated the relationship between malnutrition, derived by indices such as MNA-LF, MNA-SF, GNRI, PNI, or CONUT score, and health outcome in older patients after hip fractures; (ii) used a casecontrol, prospective or cross-sectional study design; (iii) reported odds ratio (OR), relative risk (RR), or hazard ratio (HR) estimated with 95% confidence intervals (CIs).
For each potentially included study, two investigators independently carried out the selection, data extraction, and quality assessment.Disagreements were resolved by discussion or in consultation with a third author.Although useful to have background information, reviews and meta-analyses were excluded.No studies were excluded for weakness of design or data quality.

Data Extraction and Quality Assessment
For each selected study, we extracted the following information: first author's last name, year of publication, country, study design, sample size, population characteristics (sex, age), duration of follow-up for cohort studies, type of health outcome evaluated (mortality, mobility, changes in living arrangements, and postoperative complications), health outcome assessment method, type of nutritional assessment and categories of nutrition (at risk of malnutrition, malnourished), risk estimates with 95% CIs for the different categories of nutrition, p-value for trend, and confounding factors adjustment.When multiple estimates were reported in the article, we extracted those adjusted for the most confounding factors.The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the literature for cohort and case-control studies using a 9-star system, as shown in Supplementary Table S2.The full score was 9 and a total score ≥7 was used to indicate a high-quality study [19].

Statistical Analysis
The estimated overall effect-size statistic was the average of the logarithm of the observed OR associated with the risk of malnutrition or malnourishing versus the normal state of nutrition.If the reference category was not normal, we reported the results in this form.
Concerning outcome, if it was presented in a positive form such as "survival" or "free walking ability", the results were inverted or obtained from data extracted from the original text to obtain a negative outcome ("mortality" or "decreased walking ability").
Change in living arrangements refers to an increase in level of care: living independently at home, living at home with organized home care, living in assisted living accommodation, and living in an institution.
The analysis was performed using the random-effects model to calculate the summary OR and 95% CIs.If the study reported mortality outcome as HR, OR with 95% CI was calculated from data extracted from the original text.The overall analysis of Any Health Outcome was conducted using OR, but for mortality, it was performed using both OR and HR separately.
We restricted this analysis to the following nutritional indexes: MNA-LF, MNA-SF, GNRI, PNI, and CONUT score, and to the following health outcomes: mobility, mortality, living arrangements, and postoperative complications, both overall and for different followup periods.
Stratification analysis for at risk of malnutrition and malnutrition groups was performed for observations with MNA and MNA-SF nutritional indexes, while those with GNRI, PNI, and CONUT score were included in the overall analysis.
An additional stratification was carried out for the study design (case-control or cohort study) and for age over 75 years.
The chi-square-based Cochran's Q statistic and the I 2 statistic were used to evaluate heterogeneity in results across studies [20].
We used the methods of Begg and Mazumdar [22] and Egger et al. [23] to detect publication bias.Both methods tested for funnel plot asymmetry, with the former being based on the rank correlation between the effect estimates and their sampling variances and the latter on a linear regression of a standard normal deviate on its precision.
If a potential bias was detected, we further conducted a sensitivity analysis to assess the strength of combined effect estimates, the possible influence of the bias, and to have the bias corrected.We also conducted a sensitivity analysis to investigate the influence of a single study on the overall risk estimate, by omitting one study in each turn.We considered the funnel plot to be asymmetrical if the intercept of Egger's regression line deviated from zero, with a p-value < 0.05.
The analyses were performed using the ProMeta 3 statistical program and the calculations on data extracted from the original papers were performed using STATA 13.

Study Selection
The literature search revealed 68 studies from the PubMed database, 47 from Web of Science, and 64 from Scopus.
After removing duplicates (n = 55), we identified 124 records screened for title and abstract revision (Figure 1).Among these, 76 articles were excluded (reviews, pooled or meta-analysis, commentary, and case studies).Therefore, 48 studies were subjected to full-text revision.We selected 5 additional items through the reference lists of both selected articles and recent relevant reviews .
Subsequently, 17 articles were also excluded because they did not meet the inclusion criteria as follows: 6 studies were not observational studies, 2 studies did not evaluate the impact on hip fracture, 3 studies did not consider the nutritional assessment, 3 studies did not investigate the association between nutritional assessment and outcomes, 2 studies did not report subjects aged ≥ 65 years old, and 1 study did not report the outcome.Therefore, 48 studies were subjected to full-text revision.We selected 5 additional items through the reference lists of both selected articles and recent relevant reviews .
Subsequently, 17 articles were also excluded because they did not meet the inclusion criteria as follows: 6 studies were not observational studies, 2 studies did not evaluate the impact on hip fracture, 3 studies did not consider the nutritional assessment, 3 studies did not investigate the association between nutritional assessment and outcomes, 2 studies did not report subjects aged ≥ 65 years old, and 1 study did not report the outcome.
Changes in living arrangements or in mobility level were collected by telephone interview [34,43,49,56], using the Functional Independence Measure-locomotion (FIM-L) Scale in one study [70].Postoperative delirium was evaluated according to the criteria by the Confusion Assessment Method (CAM) [39,51].
The follow-up considered in this analysis was 1-45 months.In particular, the followup for mortality was at ≤1 month in 4 studies, ≤3 months in 6 studies, ≤4 months in 8 studies, ≤6 months in 8 studies, and ≤12 months in all studies, except 1 study [64]; for mobility, follow-up was at ≤1 month in 2 studies, ≤4 months in 5 studies, and ≤12 months in all studies; for living arrangements, follow-up was at ≤1 month in 1 study, ≤4 months in 2 studies, and ≤12 months in all studies; and for complications (postoperative delirium), follow-up was only at ≤1 month.
In one study [64], the follow-up period was up to 45 months, so it was included in the overall analysis of any health outcome and mortality, but not in the follow-up stratification.One article [67] reported OR for "lower GNRI", with no reference group; therefore, it was included only in the overall analysis of any health outcome and mortality.In one paper [70], the reference group was normal/mild, so it was not included in the stratification analysis, but only in the overall analysis of any health outcome and mobility.

Meta-Analysis
A comprehensive meta-analysis was conducted to investigate the association between nutritional status and various health outcomes among older patients with hip fractures.The analysis included the comparison between malnutrition, at-risk status, and all other nutritional categories, while the health outcomes examined included mortality, living arrangements, mobility, and postoperative delirium, as shown in Table 2.The overall analysis revealed a significant association between being in one of the risk categories of the nutritional tools examined and adverse health outcomes (OR = 2.42; 95% CI 2.07-2.83;p ≤ 0.05).The odds ratio showed an increasing trend with longer follow-up periods (OR = 1.70; 95% CI 1.36-2.13;p ≤ 0.05 at ≤1 month, OR = 1.86; 95% CI 1.50-2.32;p ≤ 0.05 at ≤3 months, OR = 2.29; 95% CI 1.90-2.75;p ≤ 0.05 at ≤4 months, OR = 2.40; 95% CI 1.99-2.91;p ≤ 0.05 at ≤6 months, OR = 2.50; 95% CI 2.11-2.97;p ≤ 0.05 at ≤1 year).
Figure 2 shows the forest plots of the selected studies that examined the associations between nutritional status and outcome at 1 month, 4 months, and 1 year.
Furthermore, stratification by age group revealed significant findings in both any health negative outcome and mortality throughout the intervals of follow-up, while stratification by study type revealed significant findings in both case-control and cohort studies throughout the intervals of follow-up.Despite variations in the number of studies included, with cohort studies outnumbering case-control studies, the significance of the association remained consistent across study designs.
Because of the small amount of data, no further stratification according to gender, nutritional assessment, and different types of management of hip fractures were possible.

Sensitivity Analysis and Publication Bias
Table 2 reports results of both heterogeneity and publication bias tests.Considering the pooled data, on the basis of funnel plot symmetry for all outcomes), evidence of publication bias was detected at 1 month, 3 months, 4 months, 6 months, and 1 year.Accordingly, the corresponding statistical publication bias evaluation resulted in the p-value being significant for Begg/Egger's test.
When results were stratified according to the specific outcome, a significant publication bias was observed only in mortality HR (Overall: Egger 0.005, Begg 0.022; 1-month All: Egger 0.12, Begg 0.042; 4-month All: Egger 0.011, Begg 0.020; 12-month All: Egger 0.007, Begg 0.023) and living arrangements (1-month All: Egger 0.035; 4-month All: Egger 0.00, Begg 0.002; 12-month All: Egger 0.00, Begg 0.01).No publication bias was detected in complication and mobility outcomes and in subgroup population aged >75 years.In addition, when results were stratified according to the type of outcome, a significant publication bias was observed only in the cohort studies on mortality HR (1, 4, and 12 months) and mortality OR (1 month).
A sensitivity analysis excluding Helminen 2017 [43], which caused asymmetry of the funnel plot, produced a combined risk estimate of:

Discussion
To the best of our knowledge, this is the first systematic review and meta-analysis to summarize the relationships between malnutrition and various health outcomes in older adults with hip fractures at different follow-up intervals.We considered data regarding all health outcomes and mortality, mobility, living arrangements, and complications, and analyzed them both together and separately for different follow-up intervals.Comparable results were observed in an earlier systematic review regarding the correlation between malnutrition and various clinical outcomes among hip fracture patients, including mortality rates, functional status, increased need for assisted living arrangements, and mobility levels [7,8].We found a statistically significant association between malnutrition and any-health-negative-outcome risk in older subjects with hip fractures for all follow-up periods, with an increasing risk for longer follow-up periods.Malnutrition significantly increased any negative health outcome risk by 70% at 1 month to 250% at 1 year.While the malnourished category consistently showed significance since the first month of followup (OR = 3.01; 95% CI 1.75-5.17;p ≤ 0.05), the at-risk category emerged as significant from the fourth month of follow-up and did so progressively over time, suggesting a potential window for nutritional interventions to mitigate adverse outcomes following hip fracture.These findings underscore the critical role of nutritional status in influencing health outcomes among older individuals with hip fractures and suggest the importance of targeted interventions to improve nutritional status.With widespread rising life expectancy, there will be even more public health concern and an increasing need for initiatives in order to reduce this alarm.
The integration of both rehabilitation and nutritional therapy in older patients with hip fractures is a key strategy, resulting in decreased mortality and fewer postoperative complications, while also improving grip strength [77].
Therefore, it is advisable to endorse enhanced nutritional support alongside rehabilitation for individuals aged 65 years and older who have experienced hip fractures, aiming to mitigate mortality rates, minimize complications, and enhance ADL functionality [78].
We primarily focused on the association between hip fracture and malnutrition, overlooking the primary causes of hip fractures in older people: the role of diet and of osteoporosis.In fact, it is noted that diet is linked to the risk of osteoporotic fractures and plays a role in osteoporotic fracture healing and retaining their independence during osteoporosis prophylaxis [8,79,80].

Stratification Based on the Type of Outcome
Examining the mortality outcome, we observe a decline in the hazard ratio as the follow-up duration extends, with significance in the risk emerging noticeably from the fourth month onward, while the odds ratio concerning mortality rises with prolonged follow-up periods.The significance of living arrangements as an outcome becomes apparent from the fourth month, although it is important to underline the limited observations in the first month and the likelihood of patients still being hospitalized during this period.Similarly, the risk of declined mobility is significant from the fourth month, taking into account the probability of patients remaining hospitalized within the initial month.Lastly, postoperative delirium risk is significant in the only follow-up period available.

Mortality
Our results are consistent with those of two prior meta-analyses, which found that being at risk of malnutrition and malnourished nutritional status according to MNA were both significantly associated with higher total mortality [17,81], and that patients with low GNRI or low MNA-SF scores had a significantly higher risk of mortality compared to those with higher scores.Other studies included in the systematic review found a significant correlation between nutritional status and mortality from a qualitative point of view: at risk of malnutrition/malnourished status is negatively correlated with 3, 6, and 12 months mortality according to MNA [48], and with 6 months mortality according to CONUT score [50] and GNRI [59,71].

Postoperative Complications
A recent meta-analysis investigating the association between preoperative PNI and the incidence of POD in adult patients receiving surgery under general anesthesia demonstrated that a lower PNI was correlated with a higher risk of POD [82].
Other studies included in our systematic review evaluating postoperative complications such as urinary tract infection, heart failure, surgical site infection, refracture, pneumonia, arrhythmia, enteritis, liver dysfunction, implant failure, acute myocardial infarction, venous thromboembolism, confusion, delirium and dementia, decubitus, and the risk of falls found a significant correlation with GNRI and CONUT score [54,59,73].

Mobility
A previous systematic review highlighted that interventions aimed at enhancing mobility post-hip fracture may result in clinically significant improvements in mobility and walking speed, both during hospitalization and in post-hospital settings, compared to standard care practices [83].
Studies included in the systematic review evidenced how decreased mobility level at discharge is significantly associated with MNA-SF, GNRI [45], and PNI [76].
Walking speed (m/sec) 14 days postoperative or at discharge is significantly lower in malnourished (MNA-SF) and major-risk and mild-risk patients (GNRI).
Also, rehabilitation effectiveness calculated using the FIM Scale is significantly lower in malnourished patients according to MNA-SF and GNRI [45,46], and they were more likely to be unable to walk 6 months postoperatively [58,59].

Living Arrangements
Two studies included in the systematic review discovered that those who were malnourished according to MNA [33] and GNRI [58] exhibited notably lower scores in activities of daily living (ADL) within 48 h post-operation, upon discharge, and even at the 6-month mark post-discharge, but no significant relationship was found with discharge level of care [46].

Strengths and Limitations
The strength of this study lies in its approach of including several follow-up intervals for each outcome considered, which has not been seen before in a meta-analysis investigating health outcomes following hip fracture, as far as we are aware.Additionally, all included studies were of a high quality, scoring above 7 on the Newcastle-Ottawa Scale (NOS), ensuring reliability, even if we are aware of their possible limitations, especially in inter-rater agreement between observers of the NOS Scale [84][85][86].
Furthermore, this study stands out for evaluating various nutritional assessment tools to disclose associations with the outcomes examined.
Moreover, all articles included in this analysis were published within the last decade, reflecting the most current research in this field.However, several limitations should be acknowledged.The considerable heterogeneity observed across studies can be attributed to the diverse range of observations, nutritional assessments, and outcomes evaluated.Additionally, due to limited data availability, further stratification according to gender, nutritional assessment methods, or different types of hip fracture management was not possible.
Furthermore, while improvements in pre-surgery hospital stay and complications management have been noted, functional deterioration among hip fracture patients remains a concern in the literature.Specifically, although early surgery within 24 h or 48 h of admission has been associated with fewer postoperative complications, functional decline persists in many cases [87,88].

Figure 1 .
Figure 1.Flow diagram of the systematic literature search on malnutrition-related health outcomes in older adults with hip fractures.

Figure 1 .
Figure 1.Flow diagram of the systematic literature search on malnutrition-related health outcomes in older adults with hip fractures.

Figure 2 .
Figure 2. Forest plots of the selected studies that examined the associations between nutritional status and outcome at 1 month, 4 months, and 1 year.(A) Follow-up 1 month.(B) Follow-up 4 months.(C) Follow-up 12 months.

Table 1 .
General characteristics of included studies in the meta-analysis of malnutrition and health outcome.

Table 2 .
Results of stratified analysis of the health outcome risk estimates, after hip fracture, according to nutritional status.
a Risk estimates were calculated using the random-effects model; b Number of data used to calculate the risk.