key player or innocent bystander? A systematic review.

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Hyponatremia and aging-related diseases: key player or innocent bystander? Asystematic review.Luigia Fratangelo ( [email protected] )

Lausanne University Hospital: Centre Hospitalier Universitaire VaudoisSylvain Nguyen

Lausanne University Hospital: Centre Hospitalier Universitaire VaudoisPatrizia D’Amelio

Lausanne University Hospital: Centre Hospitalier Universitaire Vaudois

Research Article

Keywords: aging, hyponatremia, falls, dementia, osteoporosis, fractures

Posted Date: August 10th, 2022

DOI: https://doi.org/10.21203/rs.3.rs-1729582/v1

License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License

https://doi.org/10.21203/rs.3.rs-1729582/v1

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https://doi.org/10.21203/rs.3.rs-1729582/v1

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Abstract

Purpose.Hyponatremia is frequent in older age, whether it is a key player, a surrogate marker, or an innocent bystander in age related diseases is still unclear.

Method.To further understand the role of hyponatremia in falls, osteoporosis, fractures, and cognitive impairment in old patients, we conducted a systematic literaturereview. The protocol of this study is available on the International prospective register of systematic reviews (PROSPERO, number CRD42021218389).MEDLINE, EMBASE and PsycINFO database were searched. Three reviewers identi�ed studies meeting inclusion criteria and check decisions. Each study wasindependently evaluated by two reviewers, discrepancies between the two reviewers were solved by the third. Two hundred and �fteen articles were retrieved.Thirty-two were included in the review.

Results.The majority of the studies found a signi�cant association between hyponatremia and falls even after correction for confounding factors. Some studiessuggested an association between persistent hyponatremia and increased osteoporosis and fracture risk. On the contrary, the evidence of an associationbetween hyponatremia and cognitive impairment is lacking.

Conclusion.Here we suggest that hyponatremia may be regarded as a marker of unhealthy aging and a confounder rather than a causal factor or an innocent bystanderfor falls and fractures. As regards cognitive impairment, the evidence provided until now, are not su�cient to explain a real role of hyponatremia that may beregarded rather as an innocent bystander in neurodegeneration.

1 IntroductionDuring the last century, the life expectancy has doubled; however, the increase in “healthy life expectancy” has not increased superimposably (1,2). Duringaging, all systems and organs physiologically reduce their function; nevertheless, it is possible to identify a “healthy” versus an “unhealthy” aging pathway.The early identi�cation of the risk factors leading to “healthy” or “unhealthy” aging is fundamental to suggest preventive measures and early treatment.Amongst factors associated with unhealthy aging, hyponatremia has been identi�ed as a possible determinant of comorbidity and poor quality of life.Hyponatremia is the most common electrolytic disorder amongst adults aged 65 years and older; it is de�ned as a serum sodium concentration lower than135 mEq/l and indicates a relative excess of water compared to sodium, as the homeostasis of water is the main determinant of the plasma concentration ofthis cation (3). Prevalence widely varies depending on different clinical settings ranging from 7.5 to 11% amongst older community dwelling subjects, whereasit can occur in up to 53% in nursing home residents (4,5).

Amongst older subjects, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is responsible of 50% of chronic hyponatremia, howeverhyponatremia may be associated to the use of drugs such as diuretics, selective serotonin reuptake inhibitors (SSRIs) and antidepressants, and diseases asliver cirrhosis, nephropathies, adrenal insu�ciency, congestive heart failure and hypothyroidism (6). In older subjects, hyponatremia is often chronic and rathermild with a serum sodium between 130 and 135 mEq/l (7).

While severe acute hyponatremia is a well-known cause of neurological symptoms due to cerebral edema, older adults with mild and moderate hyponatremiado not develop speci�c symptoms, thus the diagnosis is often missed or delayed. Increasing evidences suggest that hyponatremia may be associated withpoor clinical outcomes in older subjects including falls (8), osteoporosis (9), fractures (10), neurocognitive disorders (11), increased morbidity and mortality(12). However, it is not clear if hyponatremia plays a causal role in these conditions or may be rather regarded as a surrogate marker of poor health andunhealthy aging.

The association between hyponatremia and increased risk of falls has been explained mainly by the impaired balance and the attention de�cit associated tothis electrolytic disorder (8,13). This has been further supported by experimental models showing that hyponatremia causes gait abnormalities via theincrease in extracellular glutamate concentration due to astrocytic glutamate decreased uptake (14). Beside the effects of hyponatremia per se, some drugsassociated with reduced serum sodium (e.g., SSRIs) may cause sensory and motor de�cits increasing the risk of falls; in fact, these drugs have beenassociated to falls and fractures even in the absence of hyponatremia (15).

Hyponatremia has also been associated to increased fracture risk, this is only partially explained by the increased risk of falls (7,9); besides this mechanisticassociation, hyponatremia may cause an imbalance in bone turnover with an increased risk of osteoporosis, being, per se, a causal factor for osteoporosisand fragility fractures. However, association between hyponatremia and impaired bone turnover leading to osteoporosis has been clearly demonstrated only inanimal models (6,16,17). In humans, association studies do not fully support a direct effect of hyponatremia on bone density (3,18,19), and hyponatremia hasrather been interpreted as general marker of poor health status more than an independent risk for fractures (20).

Regarding cognitive impairment, in humans, data are sparse (8,12), worse cognitive and functional tests have been showed in hyponatremic older subjects asrespect to non-hyponatremic age-matched controls (7,12). A possible explanation may be the reduced synthesis glutamate, demonstrated in animal models

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(21).

Some studies focused on the association between increased mortality and hyponatremia (3,9,20,22,23), suggesting that, this electrolytic disorder, may beregarded rather as a general marker of poor health status than as a causal factor of unhealthy aging.

The aim of this systematic review is to explore whether hyponatremia may be considered rather a key player, a surrogate marker, or an innocent bystander inthe occurrence of falls, fractures, and cognitive impairment.

2 Materials And Methods

2.1 Eligibility criteriaStudies included in this systematic review answered to the research question structured by the following PICO (Participants, Intervention, Comparator,Outcomes) format:

Participants

older adults de�ned as 65 years of age and older diagnosed with hyponatremia.

Interventions

studies unraveling the association between hyponatremia and

- falls

- osteoporosis with or without fractures

- dementia.

Comparator

adults aged 65 years and older without hyponatremia.

Outcomes

risk of falls, of osteoporosis with or without fractures and of dementia.

Study design

we included English-language peer-reviewed observational and intervention studies, clinical trial, prospective and retrospective controlled cohort studies, case-controlled studies without limitations regarding the date of publication. Only studies in humans have been reviewed.

2.2 Information source and search strategyWe carried out this systematic review in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). The protocol ofthis study is available on the International prospective register of systematic reviews (PROSPERO, number CRD42021218389, https://w PROSPERO, numberCRD42021218389ww.crd.york.ac.uk/PROSPERO/display_record.php?RecordID = 218389). The MEDLINE, EMBASE and PsycINFO database were searched forrelevant studies using the following terms: (("Aged"[Mesh] OR "Frail Elderly"[Mesh]) AND "Hyponatremia"[Mesh] AND ("Accidental Falls"[Mesh] OR ("Dementia"[Mesh] OR "Frontotemporal Dementia"[Mesh] OR "Mental Status and Dementia Tests"[Mesh] ) OR "Osteoporosis"[Mesh] OR ("Fractures, Bone"[Mesh] OR"Fractures, Spontaneous"[Mesh] OR "Osteoporotic Fractures"[Mesh]). The search strategy is publicly available at https://PubMed.ncbi.nlm.nih.gov/?term=%28%28%22Aged%22%5BMesh%5D+OR+%22Frail+Elderly%22%5BMesh%5D%29+AND+%22Hyponatremia%22%5BMesh%5D+AND+%28%22Accidental

2.3 Study selectionThree reviewers working independently identi�ed studies meeting criteria for inclusion and check decisions. Two reviewers independently evaluated eachstudy; discrepancies between the two reviewers were solved by the third. The �nal search was done on August 8, 2021. All the papers retrieved by the searchresponding to inclusion/exclusion criteria were included, biases were evaluated for each article and noted in a developed database. Biases were evaluatedaccording with (24).

3 Data Extraction And AnalysisTwo hundred and �fteen articles were retrieved by the search strategy: 107 from PubMed + 61 from EMBASE + 47 from PsycINFO. After removing theduplicates, we retained 135 articles for the systematic revision. We excluded 94 articles for violation of eligibility criteria; hence, 41 full text articles werereviewed as previously described. After reading the full text article, nine articles (25–33) were excluded as non-relevant for the research question (Fig. 1).Papers selected for the review were published between 2002 and 2021. Discrepancies occurred for 3 out of 41 (6.5%) studies and were solved by the thirdreviewer.

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From each study, we extracted: publication year, design of the study, participants number, number of hyponatremic and non-hyponatremic patient, mean age,gender, comorbidities and characteristic of participants, main outcome, scores, methods used to de�ne the outcomes and results.

4 Results

4.1 Hyponatremia and FallsEleven studies published between 2006 and 2019 were included (3,8,12,34–41). The majority were retrospective studies, one was a prospective population-based cohort study (3) and one was a prospective observational study (40) (Table 1).

Table 1Hyponatremia and falls. The table shows the characteristics of the studies included in the review.

Study Study design De�nition ofhyponatremiaused

Timing of sodiummeasurement

Participants

(number)

Age ofparticipants(years)

Gender Scores Main outcomes

Rennebooget al.2006(8)

Case-control Serumsodium

< 132 mEq/l

At admission and after72 hours intervals

366 70 (14)

Mean (SD)

56.56%F

TTW Incidence of falls in MED

Hoorn et al.2011 (3)

Prospectivecohort

Serumsodium < 136mEq/l

Single at baseline 5208 70.3 (9.1)

Mean (SD)

61.5%F

- Incidence of fractures,falls, mortality in thecommunity

Gosch et al.2012(12)


< 135 mEq/l

Single at admission 2880 78.6 (6.98)

Mean (SD)

75.6%F

CCI,CIRS,ADL,TMT,TUG

Effect of hyponatremiaon CGA in patientsadmitted to the GEMU

Ahamed etal.,2014(34)


≤134 mE/l

Single at admission 486 80.8 (7.63)Mean (SD)

59.3%F

CCI Incidence of falls inhyponatremic patientsadmitted under GIMU

Ganguli etal.2015(35)

Retrospectivechart review

Serumsodium

< 136 mEq/l

At baseline, at least 2 ormore than 6 consecutivemeasurements

608 84.3 (9.3)

Mean (SD)

77.1%F

CCI Incidence of falls,fractures dues to falls,hospitalization, mortalityin community-dwellingelderly

Rittenhouseet al.2015(36)

Cross-sectional

Serumsodium

< 135 mEq/l

Single at admission 2370 80 (74–86)

Median(IQR)

60.1%F

- Prevalence ofhyponatremia in fallersand mortality in patientadmitted to Level IIgeriatric trauma center

Tachi et al.2015(37)

Cross-sectional

Serumsodium

< 135 mEq/l

Single at admission 2948 64.5% aged65 yo orolder

41.1%F

- Prevalence ofhyponatremia inhospitalized patientsand effect on the risk offalls

Harianto etal.2017(38)


< 134 mEq/l

Single at admission 261 82.85(7.06)

Mean (SD)

41.4%F

- Prevalence ofhyponatremia andincidence of falls in in-hospitals patients

Kuo et al.2017(39)

Cross-sectional

Serumsodium

< 135 mEq/l

Single at admission 2494 ≥ 65 yo (= elderly).

20–64 yo(= adult)

63.2%F

- Prevalence ofhyponatremia in fallers,mortality in patientsadmitted to Level Itrauma center

Hosseini etal.2018(40)

Prospectivecohort

Serumsodium

≤ 137 mEq/l

Single at baseline 1113 68.6(6.8)

Mean (SD)

44.1%F ADL,BBS

Incidence of bonefracture and falls

Boyer et al.2019(41)

Crosssectional

Serumsodium

< 136 mEq/l

Single at admission 696 86.1 (5.6)Mean (SD)

63.1%F

CGA,ADL,SEGA

Prevalence of mildchronic hyponatremia infallers and not fallersadmitted to the MUPAunit

CGA, comprehensive geriatric assessment. ADL, Activity of Daily Living. SEGA, Frailty score on the Short Emergency Geriatric Assessment. CCI, CharlsonComorbidities Index. CIRS, Cumulative Illness Rating Scale. IQR, interquartile range. MED, Medical Emergency Department. GIMU, General Internal MedicineUnit. ISS, Injury Severity Score. MUPA, Médecine d’Urgence de la Personne Agée. GEMU, Geriatric Evaluation and Management Unit. TMT, Tinetti MobilityTest. TUG, Timed Up & Go Test. TTW, Total Travelled Way. BBS, Berg Balance Scale.

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Except for the study from Hosseini and coll. (40), all the studies evaluated the role of hyponatremia after adjusting for confounders as age, gender, medicationand comorbidities in multivariate analysis.

Almost all the studies analyzed hyponatremia as resulted from a single measurement, only one study (35) analyzed possible differences between initial andpersistent hyponatremia on the incidence of falls, fractures related to falls, hospitalization and mortality. Persistent hyponatremia was de�ned as two or moreblood tests showing hyponatremia during a six-month period.

All the studies except for (40), used the standard 135 mEq/L in order to de�ne hyponatremia. The above mentioned study (40) de�ned as hyponatremicsubjects with serum sodium ≤ 137 mEq/L.

An important predictor of falls was the female gender (OR 1.62, 95% CI 1.32–1.99, p < 0.001) in (36). Boyer and coll. (41) made a similar observation �ndingthat, among fallers, females were older and more dependent than males.

Concerning the studies’ settings, only three articles focused on in-hospital falls (37,38,42). Amongst those, two found that hyponatremia increases the risk ofin-hospital falls of 1.8-2 folds (37,38). However, Harianto and coll. (38) found no change in the prevalence of falls according to hyponatremia severity (p = 0.267); whereas, according with Tachi and coll. (37) patients with mild hyponatremia (sodium > 132 mEq/l) did not have an increased risk of falls.

Almost all the studies found that hyponatremia was independently associated with increased risk of falls, with the exception of Hosseini and coll. (40) whodid not �nd any difference in the incidence of falls, nor in the static and dynamic balance abilities between hyponatremic and normonatremic patients.According to these authors, these results could be explained by the exclusion from the study of frail patients and of subjects with long-term use of diuretics.

All the studies investigated the role of possible confounders, in particular the burden of comorbidities and functional limitation due to frailty (43). However,functional impairment and presence of frailty was assessed with different methods. Ganguli and coll used the Fried Index (35), Boyer and coll. (41) used amore complete evaluation including the Frailty Score, the Short Emergency Geriatric Assessment and the Activity of Daily Living (ADL), whereas Gosch andcoll. (12) used only the ADL scale, without considering frailty scores. Comorbidities were assessed using the Charlson Comorbidities Index (CCI) in all the threestudies (12,34,35).

In several studies, subjects with hyponatremia were older, had increased prevalence of neurological disorder (chronic dementia, history of stroke, Alzheimer’sdisease, Parkinson’s disease), of hematologic disorder, of cardiovascular disease (34,36,37,39). Despite the increased presence of comorbidity inhyponatremic subjects, the association with falls was signi�cant in spite of the corrections applied to possible confounding factors.

Concerning medications, two studies (3,34) found a higher prevalence of diuretics use among hyponatremic patients: 31.1% in hyponatremic vs 15.0% incontrols, p < 0.001 in (3) and 58% in hyponatremic vs 48.6% in controls, p < 0.037 in (34). However, in the latter, fallers exhibited a less prevalent use of diuretic.Furthermore, in-hospital falls have been inversely correlated to diuretics as well as with cardiovascular disease (38). This result has been explained by theadoption of a dedicated multidisciplinary program targeting the risk of falls in the unit concerned.

4.2 Hyponatremia, osteoporosis, and fracturesTwenty articles published between 2008 and 2020 were included (3,9,18–20,35,36,40,44–55). Three were prospective cohort study (3,20,40,51). The otherswere retrospective studies (9,18,19,35,36,44–55), and one included both a retrospective and prospective part (20). One study included only men (51) and twoonly women (18,50) (Table 2).

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Table 2Hyponatremia and osteoporosis and fractures. The table shows the characteristics of the studies included in the review.


Time of sodiummeasurement

Participants

(number)


Gender Scores Main outcome

GankamKengne etal. 2008(9)


< 135 mEq/l

Single at admission(pretreatment)

513 81(8)

Mean (SD)

74.1%F

- Prevalence ofhyponatremia infractures.

Sandhu etal.2009(79)

Cross-sectional

Serumsodium

< 135 mEq/l


Mean (SD)

75.3%F

- Incidence ofhyponatremia inpatient with fracture

Kinsella etal.2010(18)

Cross-sectional

Serumsodium

< 135 mEq/l

Within 1 year before DXA 1408 61 (11)

Mean (SD)

100%F

BMD,DXA

Incidence of fractures.

Chow et al.2011(45)

Retrospectivecohort

Serumsodium

< 135 mEq/l

Record of hyponatremia 439 76(9)

Mean (SD)

70.4%F

- Prevalence of fracturein patients withthiazide-inducedhyponatremia.

Hoorn et al.2011[3]

Prospectivecohort

Serumsodium

<136 mEq/l


Mean (SD)

61.5%F

- Incidence of fractures,falls, mortality in thecommunity

Tolouian etal.2012(46)


< 135 mEq/l


Mean (SD)

63.1%F

- Prevalence ofhyponatremia in hipfracture.

Arampatziset al.2013(47)

Cross-sectional

Serumsodium

< 132 mEq/l

Single at admission 10823 73(12)

Mean (SD)

63% F - Prevalence of fracturesin hyponatremic (loopdiuretics users).

Hagino etal.2013(48)


< 135 mEq/l

Single at admission 512 86.7(6.6)

Mean (SD)

75.5%F

- Prevalence ofhyponatremia at in hipfracture.

Afshinniaet al.2015(49)

Cross-sectional

Serumsodium

≤ 135 mEq/l

Time-averaged 24784 61 (14)

Mean (SD)

81.6%F

BMD,DXA

Prevalence ofosteoporosis.

Ganguli etal.2015(35)

Retrospectivechart review

Serumsodium

< 136 mEq/l

At baseline, at least 2 ormore than 6 consecutivemeasurements

608 84.3 (9.3)Mean (SD)

77.1%F

- Incidence of falls,fractures dues to falls,hospitalization,mortality.

Holm et al.2015(50)

Retrospectivecohort

Serumsodium

< 136 mEq/l


Mean (SD)

100%F

BMD,DXA


Jamal et al.2015(51)

Prospectivecohort

Serumsodium

< 135 mEq/l


Mean (SD)

100%M

BMD,DXA

Prevalence ofmorphometricfractures.

Kruse et al.2015(19)

Cross-sectional

Serumsodium

< 135 mEq/l

Within 14 days before orafter DXA

1575 63.13(13.6)

Mean (SD)

77.2%F

BMD,DXA


Rittenhouseet al.2015(36)

Cross-sectional

Serumsodium

<135 mEq/l

Single at admission 2370 80 (74–86)

Median(IQR)

60.1%F

- Prevalence ofhyponatremia in fallersand mortality in patientadmitted to Level IIgeriatric trauma center

Usala et al.2015(52)


< 135 mEq/l

At list 1 measurement 139594 65.9 (14.7)

Mean (SD)

88.3%F

ICD-9-CM

Incidence ofosteoporosis andfragility fractures.

BMD, Bone mineral density. DXA, Dual energy X−ray Absorptiometry. ICD−9, International Classi�cation of Disease, ninth revision, code 733 forosteoporosis.

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Time of sodiummeasurement

Participants

(number)


Gender Scores Main outcome

Ayus et al.2016(53)

Retrospectivecohort


At least on 2 or moreconsecutivemeasurements for > 90days

31527 78(12)

Mean (SD)

71.5%F

- Incidence of hipfracture.

Hosseini etal.2018(40)

Prospectivecohort

Serumsodium ≤ 137 mEq/l


Mean (SD)

44.1%F

BMD,

DXA

Incidence of bonefracture and falls.

Adams etal.2019(54)

Retrospectivecohort


Time-averaged 341003 63.3

Median

67% F BMD,DXA


Nigwekar etal.2019(55)

Case-control Serumsodium < 135mEq/l

At least twomeasurements separatedby at least 90 days

5751 84 (9)

Mean (SD)

61% F - Prevalence ofhyponatremia in hipfracture.

Schiara etal.2020(20)

Case-controlandprospectivecohort


Single at admission 2768

(Case-control)

284(cohort)

83(7)

Mean (SD)

77.8%F

- Prevalence ofhyponatremia andhypokalemia, mortality.

BMD, Bone mineral density. DXA, Dual energy X−ray Absorptiometry. ICD−9, International Classi�cation of Disease, ninth revision, code 733 forosteoporosis.

Most of the studies considered a single serum sodium measurement at admission or at baseline visit. Some studies measured sodium in the months or yearspreceding the outcome measure (35,49,52–55) since hyponatremia is a condition that persist if uncorrected (49).

Some studies suggested that mild hyponatremia (130 to 134 mEq/l) was associated with fractures owing to a decrease in Bone Mineral Density (BMD)(18,50,51). These results were not con�rmed by Hoorn and coll. (3) who did not �nd a lower BMD among older subjects with mild hyponatremia in the largecohort of the Rotterdam study. The authors hypothesized that a severe degree of hyponatremia may be associated to osteoporosis; however, in their studyonly 1.5% of subjects were affected by severe hyponatremia. Similar results were found only by Hosseini and coll. (40), in this study, the mean serum sodiumconcentration was 140 mEq/l, and the threshold of hyponatremia was �xed at 137 mEq/l.

The studies focused on persistent hyponatremia (35,49,52–55) found an increase in osteoporosis risk in the adjusted models varying from OR 1.13–2.12 (49)to OR 4.61(52). Within the above mentioned studies osteoporosis was de�ned as a decrease of bone mineral density (BMD) measured with bone densitometry,according with the standard NHI de�nition (56).

4.3 Hyponatremia and cognitive impairmentFive articles published between 2006 and 2021 were included (12,33,57–59). Three studies were prospective (57–59) and two retrospective (12,33) (Table 3).The studies were highly heterogeneous because of different study design, population included, de�nition of hyponatremia adopted, different test used toevaluate cognitive impairment, and different outcomes analyzed.

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Table 3Hyponatremia and cognitive impairment. The table shows the characteristics of the studies included in the review.


Timing ofsodiummeasurement

Participants

(number)

Age ofparticipants

(years)

Gender Cognitive Scores Main outcome

Chung etal., 2017[27]

Retrospectivecohort

According toICD-9-CM, nofurtherde�nition

Single atbaseline

24445 No. of subjects < 65 yrs:

1797 (36.7%).

No. of subjects > 65 yrs: 3103(63.3%)

44.8%F

Dementiadiagnosedaccording withICD-9-CM

Hyponatremia as apredictor of dementia

C.Fujisawaet al.,2021(59)

Prospectivecohort


Single atbaseline

2982 82.0 (76.0–84.0)in hyponatremicvs 79.0 (75–83)innormonatremic

Median yrs (IQR)

48% F MMSE, FAB, Digitspan forward,Digit spanbackward,Category �uency,Logical memory

Association betweenhyponatremia andcognitive impairment,muscle mass,physicalperformance

Gosch etal., 2012(12)

Case-control Serumsodium < 135mEq/l

Single atadmission

2880 78.6 (6.98)

Mean yrs (SD)

75.6%F

MMSE, ClockCompletion,

Effect ofhyponatremia onCGA

Pereiraet al.,2006(57)

Prospectivecohort


Single atbaseline

306 74 (8.7)

Mean yrs (SD)

50.33%F

BLAD Frequency oflaboratoryabnormality in MCIand dementia

Suárezet al.,2020(58)

Prospectivecohort


Single atadmission

180 68 (61–78,cases), 72 (65–78) controlsMedian yrs (IQR)

52.31%F

MMSE, DemTectTest, Trail MakingTests A and B

Differences incognitiveperformancesbetween groups, andbefore and aftertreatment

MMSE, Mini Mental State Examination. FAB, Frontal Assessment Battery. CGA, Comprehensive Geriatric Assessment. TMSE, Thai Mental StateExamination. BLAD, Battery of Lisbon for the Assessment of Dementia. MCI: Mild Cognitive Impairment. DemTect, Dementia Detection.

Concerning the de�nition of hyponatremia, Chung and coll. (33) de�ned as hyponatremic patients coded according to International Classi�cation of Diseases,Ninth Revision, Clinical Modi�cation (ICD-9-CM), hence they do not declare a clear sodium threshold. All the studies considered a single measurement ofhyponatremia at baseline or at admission.

Only one study (59) found a signi�cant difference in the prevalence of hyponatremia according to gender, namely the authors found a lower percentage ofwomen in the hyponatremic group.

Scores applied in order to evaluate cognitive impairment where heterogeneous amongst the studies. The Mini Mental State Examination (MMSE) was appliedin three out of six studies (12,58,59). Other neuropsychological tests as Frontal assessment battery (FAB), Digit span forward, Digit span backward, Category�uency, Logical memory were used in (59); Dementia Detection Test (DemTect), Trail Making Tests A and B (TMT-A and TMT-B) were used in (58); ClockCompletion test was applied in (12).

Two studies (12,58) found a reduced MMSE in the hyponatremic subjects. In particular, Gosch and coll. (12) reported an MMSE of 26.05 ± 3.64 points in thehyponatremic group and 27.18 ± 3.15 points in normonatremic subjects (p = 0.003). In the multivariate analysis, hyponatremia (OR 1.96, 95% CI 1.05–3.68, p = 0.045) and age (OR 1.10, 95% CI 1.05-1-16, p < 0.001) were signi�cant predictors of MMSE lower than 28 (12). Similarly, Suárez and coll. (58) reported areduced MMSE in hyponatremic patients as compared to normonatremic ones (26.09 ± 4.23 versus 28.74 ± 1.94, p < 0.001). Moreover, the authors showed thatusing a more sensitive test for the diagnosis of Mild Cognitive Impairment (MCI, i.d. DemTect versus MMSE) the association between hyponatremia andcognitive impairment was more robust.

On the contrary, Fujisawa and coll. (59) showed no differences in cognition between hypo and normonatremic subjects. These authors extensively assessedcognitive abilities using different tests, namely MMSE, FAB, Digit Span forward, Digit Span backward, �uency subtest of the Hasegawa dementia scale-revised(HDS-R) and memory disorder prevalence.

5 DiscussionHyponatremia is frequent amongst aged subjects and is frequently associated with poor health status; hence, the question if it has to be considered a markerof unhealthy aging, an innocent bystander or rather a cause of disease and unhealthy aging has still not a clear answer. Here we focus on the effect ofhyponatremia on falls, osteoporosis, fractures, and cognitive impairment, we chose these subjects because they represent a heavy burden for both patientsand society and heavily contribute to unhealthy aging and frailty.

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Falls are frequent amongst old subjects, it has been reported that one subject out of three after the age of 65 years will fall each year, moreover, age increasesinjuries caused by the falls (60,61). Besides falls related injuries, falls may generate the fear of falling amongst older patients; in fact, amongst community-dwelling older fallers, the fear of falling affects between 21 to 85% of the subjects. The fear of falling have a signi�cant effect on patients’ wellbeing, leadingto reduced independence and decreased physical activity, a recent systematic review clearly showed that the fear of falling increases the development offrailty syndrome (62). Taking into account the numbers of fallers amongst older people and the consequences due to the fall itself and the fear of falling it isclear that falls have to be considered as public health problem.

Hyponatremia has been associated to an increased risk of falls by all the analyzed studies even after correction for confounding factors, only Hosseini andcoll. (40) did not con�rm this association. However, in this prospective study, some of the characteristics of the included population may be, per se, potentialconfounders. In particular, 60.3% of patients included were affected by hypertension, and the prevalence of this disease was higher in the normonatremicgroup (91.4% versus 8.6% in hyponatremic, p = 0.02). Subjects using thiazide diuretics were excluded from the study, however no details about the assumptionof other antihypertensive medication that can in�uence sodium level were provided. These factors may represent a selection bias, and may be associated toan increased incidence of falls in the controls (63,64). Moreover, the chosen value for hyponatremia (137 mEq/l), instead of the standard one of 135 mEq/lmight contributes to equalize the risk of falls between hyponatremic and normonatremic patients according with (37).

Few studies investigated other conditions associated to increased risk of falling, such as sarcopenia (65), imbalance (66) and gait variability (67). Only twostudies (35,59) measured sarcopenia, showing an higher prevalence of this disease in subjects with mild hyponatremia. Gait imbalance was assessed in threestudies (8,35,59), showing that older subjects with mild hyponatremia had balance impairment. In (8), the assessment of the gait imbalance has beenperformed using the TTW (total travelled way) test consisting of performing 3 steps on a platform, in tandem, and with open eyes. The travelled distance isobtained as the displacement of the patient centre of pressure for ten seconds. Walking speed was used instead in (35), and walking speed and one-legstanding test times in (59).

Although most studies provide evidence that there is a signi�cant independent association between hyponatremia and falls, almost all studies wereretrospective, so it is not possible to establish a causal role for hyponatremia in determining the risk of falls. Moreover, the majority of the study considered asingle time point sodium measurement, that cannot be considered as representative of the sodium level of the individual; only two retrospective studies (8,35)focused on chronic hyponatremia de�ned as hyponatremia duration ≥ 48 h (68). Ganguli and coll. (35) showed a higher incidence of falls in patients withpersistent, duration > 72 h but not in patients with initial nor transient hyponatremia. These results agree with the results obtained by two prospective studies(3,40) who did not �nd any association between hyponatremia and falls and in which a single serum sodium measurement at baseline was used.

The results of the analyzed prospective studies indicate that hyponatremia is a risk factor of falls.1

In (69) it has been estimated an yearly number of osteoporotic fractures equal to 9 million (17.8% at the hip, 18.9% at the forearm and 15.6% vertebral).Altogether, osteoporotic fractures represented worldwide 0.83% of the total chronic non-communicable disease and 1.75% of the global burden in terms ofincidence of fractures, prevalence of disabled individuals, excess mortality, and Disability Adjusted Life Years (DALYs) in Europe in the year 2000 (69). TheDALYs lost due to osteoporotic fractures was higher than for common cancers, except lung cancer (69). Hence osteoporosis and osteoporosis relatedfractures must be considered as a major obstacle to healthy aging and a severe burden for patients, families, and society. Several studies suggested anassociation between hyponatremia and osteoporotic fractures (3,9,35,44–48,52,53,55). Hyponatremia has been considered as a risk factors for osteoporosisas the skeleton storage about one third of body sodium and thus can be considered as a reservoir in case of reduction of serum sodium (70). It has beenpostulated that, in case of severe hyponatremia, sodium is mobilized from bone to maintain blood homeostasis causing matrix resorption and bone loss (6).

To unravel the relationship between sodium and fragility fractures, some studies investigated whether hyponatremia can be associated with a decreased BMDwith controversial �ndings. Two studies showed that hyponatremia is associated with fragility fractures beyond BMD (18,51) while four studies (19,49,50,54)showed an increased risk of fragility fractures as a result of a reduction of BMD. In two (49,54) out of six studies, hyponatremia was measured as time-averaged. In particular, Afshinnia and coll (49), showed that the larger the duration of hyponatremia the larger the risk of osteoporosis in the younger agegroup, thus, suggesting a time-related role of hyponatremia on the development of osteoporosis. Interestingly, in this study the risk of osteoporosis wasattenuated in the older patients as respect to the younger ones. According to the authors, age acts as a competing risk factor for osteoporosis by increasingthe number of patients with osteoporosis in the normonatremic group due to old age. This �nding is comparable to those of the Rotterdam study (3) that didnot �nd any association between hyponatremia and a lower BMD in the older subjects.

In two studies (20,40) no association between hyponatremia and fragility fractures was found. Some differences in comorbidities between hyponatremic andnormonatremic subjects may affect results representing a selection bias in (40) as previously discussed. In Schiara and coll. (20), no association between adecrease of sodium blood level and risk of fragility fractures was found, suggesting that sodium could be a marker of health status rather than playing adirect role in fracture risk. However, in this study, intravenous �uids infusions or prescribed drugs before admission in cases admitted for femoral fragilityfractures such as in the controls admitted for acute myocardial infarction at the Emergency Department may have affected the results. In (40), the use ofantihypertensive medication may in�uence bone mineral density, in particular, loop diuretics are associated with increased urinary calcium excretion and aconsequent increase of parathormone levels that induce an accelerated bone resorption (71). On the other hand, the use of angiotensin-converting enzymeinhibitors has been suggested to increased BMD thanks to the inhibition of osteoclast activation due to angiotensin I (72). Additionally, in (40) Blood UreaNitrogen (BUN) was higher in hyponatremic subjects, increased BUN is associated to a higher protein intake, that, in some studies, has been associated toosteoporosis due to a slight reduction in blood pH and a consequent increase in urinary calcium excretion (73).

All the reviewed studies provide the evidence that hyponatremia is associated with fracture risk, but the question whether hyponatremia plays a direct role infractures and bone quality remains to be answered.

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Dementia is a syndrome that affects independent living through a decline in memory, cognitive abilities, and behavior (74) and represent a public healthpriority. The prevalence and incidence of dementia are steadily increasing. The total estimated number of people with dementia was at 35.6 million worldwidein 2010 (74) and 50 million in 2018 and il will double every 20 years reaching 82 million in 2030 and 152 million in 2050 (75). It represents the second largestcause of disability for subjects of 70 years and older and the seventh cause of death (76). The estimated annual global cost of dementia that include directmedical care, social care, and informal care, is actually US$ 818 billion, and is expected to double by 2030 worldwide (76).

Hyponatremia has been studied as risk factor for neurological degeneration leading to dementia as neurological symptoms are the main manifestation ofsevere hyponatremia. However, although in acute hyponatremia the mechanism underlying the severe clinical picture observed is well known (edema andencephalopathy) in chronic hyponatremia there are few evidence causally linking hyponatremia to neurological disorders. During mild chronic hyponatremia,central nervous system settles an adaptative response involving the loss of osmolytes to prevent swelling and preserve function (77). However some of thelost osmolytes are neurotransmitters such as glutamate and taurine (21), this condition may explain the impairment of cognitive function.

Few studies focused on the impact of hyponatremia on cognition, all the studies included in this review evaluated different outcomes and used differentmethods to assess cognitive abilities, hence we found a high heterogeneity amongst the different studies. Renneboog and coll. (8) �rstly demonstrated thepresence of an attention de�cit in mild hyponatremic patients. Gosch and coll. (12) as well as Suárez and coll. (58) found a worse cognitive performancemeasured by MMSE in patients with mild to moderate hyponatremia. Despite different study design, retrospective in (12) and prospective in (58), this twostudies found very similar results in MMSE test in hyponatremic patients, 26.05 ± 3.64 in (12) and 26.09 ± 4.23 in (58). Although this interesting results, it isimportant to underline that the score obtained by both these studies is above the cut-off score (23.9/30) that distinguishes between pathological and normalperformance (78). Hence, although the difference in the MMSE score was statistically signi�cant, such a difference may not be clinically relevant.

Moreover, the prospective study by Fujisawa and coll. (59) showed no alteration in cognitive function in hyponatremic patients despite the use of a full batteryof neuropsychological tests to evaluate cognitive performance.

Due to such limited literature and con�icting results, the evidence for an association between hyponatremia and reduced cognitive performance is still lacking.To date, due to the descriptive nature of the studies, the mechanism underlying the association between hyponatremia and cognitive impairment remainsunclear. Further studies are required to understand whether cognitive impairment is rather due to the condition causing hyponatremia or if hyponatremia is acausal factor per se. The main limitation of this review is the type of studies included, due to their observational design and the high heterogeneity it was notreally possible to fully assess the biases and compare the results obtained.

6 ConclusionsReferring to Bradford-Hill criteria on causality, biological coherence suggesting a causal effect for hyponatremia was demonstrated for all the outcomestested.

Most studies provided consistent evidences for a strong association between hyponatremia and falls. Whereas, for osteoporotic fractures and cognitiveimpairment the studies showed con�icting results. The association with hyponatremia is present, although not very strong, between hyponatremia andfractures; on the contrary, the association between hyponatremia and cognitive impairments is very weak.

All the studies showed that falls, fractures, osteoporosis, and cognitive impairment are due to multifactorial causes and hence that hyponatremia may not beregarded as a speci�c cause of diseases taken into account.

As regards timing there are not su�cient evidence to temporally relate hyponatremia with falls, fractures, and cognitive impairment occurrence.

For the above-mentioned considerations, we suggest that hyponatremia may be regarded as a marker of unhealthy aging and a confounder rather than acausal factor or an innocent bystander for falls and fractures. As regards cognitive impairment, the evidences provided until now, are not su�cient to explain areal role of hyponatremia that may be regarded rather as an innocent bystander in neurodegeneration.

DeclarationsCompeting Interests: the authors declare that they have no competing interest.

Founding sources: this work received no funding.

References1. Healthy life expectancy from. age 65 | OBSAN [Internet]. [cité 14 déc 2020]. Disponible sur: https://www.obsan.admin.ch/en/indicators/MonAM/healthy-

life-expectancy-age-65.

2. Bell FC, Miller ML. Life Tables for the United States Social Security Area 1900–2100.:194.

3. Hoorn EJ, Rivadeneira F, van Meurs JBJ, Ziere G, Stricker BHC, Hofman A, et al. Mild hyponatremia as a risk factor for fractures: the Rotterdam Study. JBone Miner Res août. 2011;26(8):1822–8.

4. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol juill. 2006;17(7):1820–32.

5. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med juill. 2006;119(7 Suppl 1):30–5.

�. Verbalis JG, Barsony J, Sugimura Y, Tian Y, Adams DJ, Carter EA, et al. Hyponatremia-induced osteoporosis. J Bone Miner Res mars. 2010;25(3):554–63.

/13

7. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, et al. Clinical practice guideline on diagnosis and treatment of hyponatraemia. IntensiveCare Med mars. 2014;40(3):320–31.

�. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention de�cits.Am J Med janv. 2006;119(1):71.e1-8.

9. Gankam Kengne F, Andres C, Sattar L, Melot C, Decaux G. Mild hyponatremia and risk of fracture in the ambulatory elderly. QJM juill. 2008;101(7):583–8.

10. Ayus JC, Negri AL, Kalantar-Zadeh K, Moritz ML. Is chronic hyponatremia a novel risk factor for hip fracture in the elderly? Nephrol Dial Transplant. oct2012;27(10):3725–31.

11. Brinkkoetter PT, Grundmann F, Ghassabeh PJ, Becker I, Johnsen M, Suaréz V, et al. Impact of Resolution of Hyponatremia on Neurocognitive and MotorPerformance in Geriatric Patients. Sci Rep 29 août. 2019;9(1):12526.

12. Gosch M, Joosten-Gstrein B, Heppner HJ, Lechleitner M. Hyponatremia in geriatric inhospital patients: effects on results of a comprehensive geriatricassessment. Gerontology. 2012;58(5):430–40.

13. Gunathilake R, Oldmeadow C, McEvoy M, Kelly B, Inder K, Scho�eld P, et al. Mild hyponatremia is associated with impaired cognition and falls incommunity-dwelling older persons. J Am Geriatr Soc oct. 2013;61(10):1838–9.

14. Fujisawa H, Sugimura Y, Takagi H, Mizoguchi H, Takeuchi H, Izumida H, et al. Chronic Hyponatremia Causes Neurologic and Psychologic Impairments. JAm Soc Nephrol mars. 2016;27(3):766–80.

15. Fabian TJ, Amico JA, Kroboth PD, Mulsant BH, Corey SE, Begley AE, et al. Paroxetine-induced hyponatremia in older adults: a 12-week prospective study.Arch Intern Med. 9 févr 2004;164(3):327–32.

1�. Barsony J, Manigrasso MB, Xu Q, Tam H, Verbalis JG. Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats. Age.2013;35(2):271–88.

17. Tamma R, Sun L, Cuscito C, Lu P, Corcelli M, Li J, et al. Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia. Proc NatlAcad Sci U S A 12 nov. 2013;110(46):18644–9.

1�. Kinsella S, Moran S, Sullivan MO, Molloy MGM, Eustace JA. Hyponatremia independent of osteoporosis is associated with fracture occurrence. Clin J AmSoc Nephrol févr. 2010;5(2):275–80.

19. Kruse C, Eiken P, Vestergaard P. Hyponatremia and osteoporosis: insights from the Danish National Patient Registry. Osteoporos Int mars.2015;26(3):1005–16.

20. Schiara LAM, Moirano G, Grosso E, Richiardi L, Tibaldi M, Spertino E, et al. Hyponatremia, Hypokalemia, and Fragility Fractures in Old Patients: More thanan Association? Calcif Tissue Int juin. 2020;106(6):599–607.

21. Verbalis JG. Brain volume regulation in response to changes in osmolality. Neurosci 28 juill. 2010;168(4):862–70.

22. Sajadieh A, Binici Z, Mouridsen MR, Nielsen OW, Hansen JF, Haugaard SB. Mild hyponatremia carries a poor prognosis in community subjects. Am J Medjuill. 2009;122(7):679–86.

23. Mohan S, Gu S, Parikh A, Radhakrishnan J. Prevalence of hyponatremia and association with mortality: results from NHANES. Am J Med déc.2013;126(12):1127–37.e1.

24. Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updatedFebruary 2022) [Internet]. Disponible sur: Cochrane; 2022. .

25. Mc Causland FR, Wright J, Waikar SS. Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedicsurgery. J Hosp Med mai. 2014;9(5):297–302.

2�. Srinonprasert V, Pakdeewongse S, Assanasen J, Eiamjinnasuwat W, Sirisuwat A, Limmathuroskul D, et al. Risk factors for developing delirium in olderpatients admitted to general medical wards. J Med Assoc Thai. 2011;94 Suppl 1((Srinonprasert V.) Department of Medicine, Faculty of Medicine SirirajHospital, Mahidol University, Bangkok, Thailand.):S99-104.

27. Wong J, New RH, Wong D, Adikari S. Hyponatraemia - A potential marker of frailty and geriatric syndrome. Intern Med J. 2020;50((Wong J.; Adikari S.)Cairns Hospital, Cairns, QLD, Australia):38.

2�. Beloosesky Y, Hershkovitz A, Solovey B, Salai M, Weiss A. Hip fracture post-operation dysnatremia and Na+-courses in different cognitive and functionalpatient groups. Arch Gerontol Geriatr oct. 2011;53(2):179–82.

29. McPherson E, Dunsmuir RA. Hyponatraemia in hip fracture patients. Scott Med J oct. 2002;47(5):115–6.

30. Rocha AFB, Sá MVBDO, Elihimas Junior UF. Hyponatremia in elderly patients with fragility fractures of the proximal femur: a cross-sectional study. J BrasNefrol déc. 2019;41(4):518–25.

31. Aicale R, Tarantino D, Maffulli N. Prevalence of Hyponatremia in Elderly Patients with Hip Fractures: A Two-Year Study. Med Princ Pract. 2017;26(5):451–5.

32. Tinning CG, Cochrane LA, Singer BR. Analysis of hyponatraemia associated post-operative mortality in 3897 hip fracture patients. Injury juill.2015;46(7):1328–32.

33. Chung MC, Yu TM, Shu KH, Wu MJ, Chang CH, Muo CH, et al. Hyponatremia and increased risk of dementia: A population-based retrospective cohortstudy. PLoS ONE. 2017;12(6):e0178977.

34. Ahamed S, Anpalahan M, Savvas S, Gibson S, Torres J, Janus E. Hyponatraemia in older medical patients: implications for falls and adverse outcomes ofhospitalisation. Intern Med J oct. 2014;44(10):991–7.

/13

35. Ganguli A, Mascarenhas RC, Jamshed N, Tefera E, Veis JH. Hyponatremia: incidence, risk factors, and consequences in the elderly in a home-basedprimary care program. Clin Nephrol août. 2015;84(2):75–85.

3�. Rittenhouse KJ, To T, Rogers A, Wu D, Horst M, Edavettal M, et al. Hyponatremia as a fall predictor in a geriatric trauma population. Injury janv.2015;46(1):119–23.

37. Tachi T, Yokoi T, Goto C, Umeda M, Noguchi Y, Yasuda M, et al. Hyponatremia and hypokalemia as risk factors for falls. Eur J Clin Nutr févr.2015;69(2):205–10.

3�. Harianto H, Anpalahan M. In-hospital Falls in Older Patients: The Risk Factors and The Role of Hyponatraemia. Curr Aging Sci. 2017;10(2):143–8.

39. Kuo SCH, Kuo PJ, Rau CS, Wu SC, Hsu SY, Hsieh CH. Hyponatremia Is Associated with Worse Outcomes from Fall Injuries in the Elderly. Int J Environ ResPublic Health. 26 avr 2017;14(5).

40. Hosseini SR, Baghitabar N, Mirzapour A, Oliaei F, Nooreddini H, Bijani A, et al. Hyponatremia, bone mineral density and falls in the elderly; Results fromAHAP study. Rom J Intern Med. 1 mars 2018;56(1):41–6.

41. Boyer S, Gayot C, Bimou C, Mergans T, Kajeu P, Castelli M, et al. Prevalence of mild hyponatremia and its association with falls in older adults admitted toan emergency geriatric medicine unit (the MUPA unit). BMC Geriatr 15 oct. 2019;19(1):265.

42. Fehlberg EA, Lucero RJ, Weaver MT, McDaniel AM, Chandler AM, Richey PA, et al. Associations between hyponatraemia, volume depletion and the risk offalls in US hospitalised patients: a case-control study. BMJ Open 7 août. 2017;7(8):e017045.

43. Espinoza S, Walston JD. Frailty in older adults: insights and interventions. Cleve Clin J Med déc. 2005;72(12):1105–12.

44. Sandhu HS, Gilles E, DeVita MV, Michelis MF. Hyponatremia and the risk of large bone fracture in elderly patients. Am J Kidney Dis. 2009;53(4):A67.

45. Chow KM, Szeto CC, Kwan BCH, Ma TKW, Leung CB, Li PKT. Fracture risk after thiazide-associated hyponatraemia. Intern Med J juill. 2012;42(7):760–4.

4�. Tolouian R, Alhamad T, Farazmand M, Mulla ZD. The correlation of hip fracture and hyponatremia in the elderly. J Nephrol oct. 2012;25(5):789–93.

47. Arampatzis S, Gaetcke LM, Funk GC, Schwarz C, Mohaupt M, Zimmermann H, et al. Diuretic-induced hyponatremia and osteoporotic fractures in patientsadmitted to the emergency department. Maturitas mai. 2013;75(1):81–6.

4�. Hagino T, Ochiai S, Watanabe Y, Senga S, Saito M, Takayama Y, et al. Hyponatremia at admission is associated with in-hospital death in patients with hipfracture. Arch Orthop Trauma Surg avr. 2013;133(4):507–11.

49. Afshinnia F, Sundaram B, Ackermann RJ, Wong KK. Hyponatremia and osteoporosis: reappraisal of a novel association. Osteoporos Int sept.2015;26(9):2291–8.

50. Holm JP, Amar AOS, Hyldstrup L, Jensen JEB. Hyponatremia, a risk factor for osteoporosis and fractures in women. Osteoporos Int mars.2016;27(3):989–1001.

51. Jamal SA, Arampatzis S, Harrison SL, Bucur RC, Ensrud K, Orwoll ES, et al. Hyponatremia and Fractures: Findings From the MrOS Study. J Bone Miner Resjuin. 2015;30(6):970–5.

52. Usala RL, Fernandez SJ, Mete M, Cowen L, Shara NM, Barsony J, et al. Hyponatremia Is Associated With Increased Osteoporosis and Bone Fractures in aLarge US Health System Population. J Clin Endocrinol Metab août. 2015;100(8):3021–31.

53. Ayus JC, Fuentes NA, Negri AL, Moritz ML, Giunta DH, Kalantar-Zadeh K, et al. Mild prolonged chronic hyponatremia and risk of hip fracture in the elderly.Nephrol Dial Transplant oct. 2016;31(10):1662–9.

54. Adams AL, Li BH, Bhandari S, Kamat S, Sundar S, Krasa H, et al. Chronic hyponatremia and association with osteoporosis among a largeracially/ethnically diverse population. Osteoporos Int avr. 2019;30(4):853–61.

55. Nigwekar SU, Negri AL, Bajpai D, Allegretti A, Kalim S, Seethapathy H, et al. Chronic prolonged hyponatremia and risk of hip fracture in elderly patients withchronic kidney disease. Bone oct. 2019;127:556–62.

5�. Osteoporosis prevention. diagnosis, and therapy. NIH Consens Statement 27 mars. 2000;17(1):1–45.

57. Pereira AF, do Couto FS, de Mendonça A. The use of laboratory tests in patients with Mild Cognitive Impairment. J Alzheimer’s Disease. 2006;10(1):53–8.

5�. Suárez V, Norello D, Sen E, Todorova P, Hackl MJ, Hüser C, et al. Impairment of Neurocognitive Functioning, Motor Performance, and Mood Stability inHospitalized Patients With Euvolemic Moderate and Profound Hyponatremia. Am J Med août. 2020;133(8):986–93.e5.

59. Fujisawa C, Umegaki H, Sugimoto T, Samizo S, Huang CH, Fujisawa H, et al. Mild hyponatremia is associated with low skeletal muscle mass, physicalfunction impairment, and depressive mood in the elderly. BMC Geriatr 6 janv. 2021;21(1):15.

�0. Freiberger E, Häberle L, Spirduso WW, Zijlstra GAR. Long-term effects of three multicomponent exercise interventions on physical performance and fall-related psychological outcomes in community-dwelling older adults: a randomized controlled trial. J Am Geriatr Soc mars. 2012;60(3):437–46.

�1. Álvarez-Barbosa F, del Pozo-Cruz J, del Pozo-Cruz B, Alfonso-Rosa RM, Rogers ME, Zhang Y. Effects of supervised whole body vibration exercise on fallrisk factors, functional dependence and health-related quality of life in nursing home residents aged 80+. Maturitas déc. 2014;79(4):456–63.

�2. de Souza LF, Canever JB, Moreira B, de S, Danielewicz, de Avelar AL. NCP. Association Between Fear of Falling and Frailty in Community-Dwelling OlderAdults: A Systematic Review. Clin Interv Aging. 2022;17:129–40.

�3. Abu Bakar AAZ, Abdul Kadir A, Idris NS, Mohd Nawi SN. Older Adults with Hypertension: Prevalence of Falls and Their Associated Factors. Int J EnvironRes Public Health. 4 août 2021;18(16).

�4. Berry SD, Kiel DP. Treating hypertension in the elderly: should the risk of falls be part of the equation? JAMA Intern Med avr. 2014;174(4):596–7.

�5. Beaudart C, Rizzoli R, Bruyère O, Reginster JY, Biver E. Sarcopenia: burden and challenges for public health. Arch Public Health. 2014;72(1):45.

��. Santos DA, Silva AM, Baptista F, Santos R, Vale S, Mota J, et al. Sedentary behavior and physical activity are independently related to functional �tness inolder adults. Exp Gerontol déc. 2012;47(12):908–12.

/13

�7. Lopez P, Pinto RS, Radaelli R, Rech A, Grazioli R, Izquierdo M, et al. Bene�ts of resistance training in physically frail elderly: a systematic review. Aging ClinExp Res août. 2018;30(8):889–99.

��. Kheetan M, Ogu I, Shapiro JI, Khitan ZJ. Acute and Chronic Hyponatremia. Front Med (Lausanne). 2021;8:693738.

�9. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int déc.2006;17(12):1726–33.

70. BERGSTROM WH. The participation of bone in total body sodium metabolism in the rat. J Clin Invest. juill 1955;34(7, Part 1):997–1004.

71. Rejnmark L, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L. Effects of long-term treatment with loop diuretics on bone mineral density,calcitropic hormones and bone turnover. J Intern Med févr. 2005;257(2):176–84.

72. Ghosh M, Majumdar SR. Antihypertensive medications, bone mineral density, and fractures: a review of old cardiac drugs that provides new insights intoosteoporosis. Endocr août. 2014;46(3):397–405.

73. Krieger NS, Frick KK, Bushinsky DA. Mechanism of acid-induced bone resorption. Curr Opin Nephrol Hypertens juill. 2004;13(4):423–36.

74. WHO. 2012. Dementia a public health priority. [Internet]. Disponible sur:https://apps.who.int/iris/bitstream/handle/10665/75263/9789241564458_eng.pdf;jsessionid=91F60603FF10908D2230F876DE20819C?sequence=1 [.

75. WHO. 2018. Towards a dementia plan: a WHO guide. [Internet]. Disponible sur:https://apps.who.int/iris/bitstream/handle/10665/272642/9789241514132-eng.pdf.

7�. WHO. 2017. Dementia: number of people affected to triple in next 30 years. W [Internet]. Disponible sur: http://www.who.int/mediacentre/news/releases/2017/dementia-triple-affected/en/.

77. Ayus JC, Achinger SG, Arieff A. Brain cell volume regulation in hyponatremia: role of sex, age, vasopressin, and hypoxia. Am J Physiol Renal Physiol sept.2008;295(3):F619–24.

7�. Folstein MF, Folstein SE, McHugh PR. « Mini-mental state ». A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Resnov. 1975;12(3):189–98.

79. Sandhu HS, Gilles E, DeVita MV, Panagopoulos G, Michelis MF. Hyponatremia associated with large-bone fracture in elderly patients. Int Urol Nephrol.2009;41(3):733–7.

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