Age-associated risk of sarcopenia, falls and fractures: results of Ukrainian cohort study

. Background . It is well-known that sarcopenia increases the risk of falls and fractures, and therefore, requires correction to improve the quality of life of elderly people. This research purposed to study the age-related changes in the sarcopenia risk, falls, and fractures in Ukrainian women in the late reproductive and postmenopausal periods. Materials and methods. We examined 573 females aged from 40 to 89 years old. The subjects were grouped by age decades and presence of high sarcopenia risk (HSR). The SARC-F questionnaire measured the sarcopenia risk, and the risk of falls using the Desmond Fall Risk Questionnaire, the 10-year probability of major osteoporotic and hip fractures was assessed by FRAX, and daily activity — according to the IADL scale. Also, we performed the hand grip strength and five-repetition sit-to-stand tests. Results . The frequency of HSR increased with age from 1.5 % in the 40–49-year-old group to 73.7 % in subjects over 80, as well as fracture and fall risks (p < 0.00001 for both indices) related to decreasing independence in the subject’s everyday life. Also, we revealed age-dependent loss of muscle strength according to the hand grip and the five-repetition sit-to-stand tests. After the adjustment of the subjects by age we found that the females with HSR had a higher risk of falls, a lower level of independence, and increased frequency and risk of osteoporotic fractures. Conclusions . Women with HSR have a higher risk of falls, fractures, and more limitations in daily living activities independently from age and body mass index. These findings request comprehensive management of older women with attention to various parameters for the increase of independence and quality of life.


Introduction
Modern demographic trends demonstrate significant aging of the global population.In the European population in 2021, persons aged 65 years and older made up one fifth of the entire population (20.8 %), 80 years and older -6 %, and according to the forecasts, their share will increase to 14.6 % in 2100 [1].The share of people of the older age groups is increasing progressively in Ukraine as well.Thus, according to the State Statistics Service of Ukraine, if in 1990 the share of people aged 65 years old and older was 12 %, in 2000 -13.9 %, then in 2021 -17.6 % [2].Increasing life expectancy is an unconditional achievement of humanity, but also a challenge for the health care system.Seeking medical help of an elderly patient with polymorbidity requires not only the treatment of the existing pathologies, but also the determination of a high risk of possible diseases in the future.Low-energy fractures are the ones of important complications in the elderly with a high impact on the quality and length of human life.According to the DALYs (Disability-adjusted life years) index, which measures the burden of the disease on society, low-energy fractures take the fourth place, yielding only to coronary heart disease, dementia, and lung cancer [3].
The main predictors of low-trauma fractures are low bone mineral density (BMD) and high risk of falls, which is associated with many diseases, but first of all, with the state of skeletal muscles [4].And, if the BMD parameters has been studied for the last 50 years, the age-related features of muscle began to be actively studied only in the 21 st century.The absence of specific complaints, clinical signs, and etiotropic treatment does not prompt specialists to start an appropriate diagnostic search, despite the sarcopenia diagnostic algorithm proposed in the updated EWGSOP2 consensus [5], which includes a step-by-step approach to determining risk, diagnosis, confirmation, and determining the severity of sarcopenia.
The term "sarcopenia" is often associated with a low body mass index (BMI), and the increase in obesity of the population distracts from the need to diagnose sarcopenia.

Оригінальні дослідження / Original Researches
The presence of sarcopenia increases the risk of falls and fractures, and therefore, requires correction in order to improve the quality and duration of life of elderly people.The recent systematic review and meta-analysis had analyzed 33 studies with 45,926 participants and showed a significantly higher risk of falls and fractures in cross-sectional, as in prospective studies compared with non-sarcopenic subjects [6].However, most of the studies included in this systematic review and meta-analysis were conducted among communitydwelling subjects with a limited number of institutionalized persons without stratification by ethnicity.Currently, there is no data about interconnection between sarcopenia and its consequences, in particular, falls and fractures in Ukrainian population, and further research is needed.Therefore, the purpose of the study was to study the age-related changes in the risk of sarcopenia, falls and fractures in women in the late reproductive and postmenopausal period.

Study design and participants
The one-center cohort study was conducted by the Department of Clinical Physiology and Pathology of the Musculoskeletal System of the State Institution "D.F.Chebotarev Institute of Gerontology of the National Academy of Sciences of Ukraine", following the tenets outlined in the Declaration of Helsinki, and with the approval of the local ethics committee (protocol No. 4 dated 12.03.2020).It was carried out within the framework of the scientific research of Institute ("Sarcopenia: risk factors, mechanisms, diagnostiсs, prevention and treatment, connection with of the musculoskeletal diseases", No. 0120U102515).
The subjects were women aged from 40 to 89 years old in late reproductive and postmenopausal periods who applied for outpatient doctor consultation for various reasons in the period from April 2021 to February 2022.Written informed consent for the participation was a mandatory condition for inclusion in the study.
From 678 examined females, 573 ones (average age 63.3 ± 10.6 years) had been selected.Exclusion criteria were oncological pathology, serious cardiovascular and respiratory diseases, movement disorders (stroke, Parkinson's disease), severe hand joint's deformations, and limb fractures before bone consolidation.For the further analysis, the women were grouped by age decades.Also, the subjects were divided into 2 groups depending on the presence of a high risk of sarcopenia.

Methods
Strength, assistance with walking, rising from a chair, climbing stairs, and falls (SARC-F) questionnaire was used for the assessment of sarcopenia risk.Also, the risk of falls was determined according to the Desmond Fall Risk Questionnaire.Ten-year probability of major osteoporotic fractures (MOFs) and hip fractures (HFs) was assessed by Fracture Risk Assessment Tool (FRAX), and daily activity -according to the Instrumental Activities of Daily Living (IADL) scale.
It is well-known that SARC-F is a widely used and simple tool for sarcopenia screening [7] that is a self-administered questionnaire that comprises questions in the following five domains: strength, assistance in walking, rising from a chair, climbing stairs, and falls.The total score ranges from 0 to 10 points and a subject with results of 4 or higher has a high risk of sarcopenia.The SARC-F sensitivity and specificity according to the EWGSOP1 or AWGS are 14-21 and 90-94 %, respectively [8].
Desmond Fall Risk Questionnaire (Desmond A.L., 2000) is a self-reported tool for the evaluation of the fall risk that consisted of 15 questions which are either positive or negative.A positive answer indicates the factors influencing the risk of falls; a negative one negates the potential risk of definite factor on falls [9].
The Lawton Instrumental Activities of Daily Living Scale (IADL) is an instrument to assess the independent living skills (Lawton & Brody, 1969).It consists of 8 domains (Ability to Use the Telephone, Shopping, Cooking, Housekeeping, Laundry, Mode of Transportation, Responsibility for Own Medications, and Ability to Handle Finances).The subjects are scored in accordance with their highest level of functioning in each category.A summary score ranges from 0 (low function, dependent) to 8 (high function, independent) for women [10,11].
The calculation of the ten-year probability of MOFs and HFs was performed using the Ukrainian version of FRAX on the official FRAX online resource (https://www.sheffield.ac.uk/FRAX) without using BMD of the femoral neck [12].
The presence of the previous low-trauma fractures was confirmed by an investigator in accordance with patient medical source or data of anamnesis.All questionnaires were translated and adapted earlier into Ukrainian [13,14].All subjects had completed the questionnaires themselves after a preliminary instruction by the researcher.
Body weight was measured using calibrated electronic balance with scale to the nearest 0.1 kg; standing height was measured using stadiometer to the nearest 0.1 cm with participants wearing light clothes and no shoes on.The body mass index (BMI) was calculated according to the generally accepted formula.
Skeletal muscle strength was assessed using the hand grip strength test, and five-repetition sit-to-stand test.Grip strength was measured using a hand dynamometer DPR-90 in seated subjects, their elbow by their side and flexed to right angles with a neutral wrist position, the dynamometer handle position 2 and provision of support underneath the dynamometer.The calculation of the mean of three trials of grip strength for each hand was performed and documented as reliable [15,16].Hand grip strength was measured by the amount of static force that hand can squeeze around a dynamometer and recorded in kilograms.The hand grip strength data were recorded separately for the left and right hands accounted for the dominance.One researcher for all performed measurements was trained in the use of the dynamometer according to this protocol and practiced the testing procedure prior to the assessments.Five-repetition sit-to-stand test.Participants were asked to stand up and sit down five times as quickly as possible, with their hands folded across their chest.The ability to perform this test reflects the coordination of the patient.The results were recorded in seconds [17,18].

Statistical analysis
Statistical testing was conducted using the Statistica 10.0 program packages Copyright © StatSoft, Inc. 1984-2001, Serial number 31415926535897, and SPSS Statistics 17.0 Copyright © Silver Egg Technology 2001.The data were expressed as the mean value and standard deviation (M ± SD) or as the median (Me) and interquartile range [LQ-UQ] depending on the normality of distribution (according to the Shapiro-Wilk test).Differences between the independent groups were determined by Student's or ANOVA (with Scheffe test) in case of normal distribution of data (for comparison of 2 or more than 2 independent groups), and Wilcoxon-Mann-Whitney test or Kruskal-Wallis analysis for multiple comparisons in non-normal data (for comparison of 2 or more than 2 independent groups, respectively).Spearman's rank correlation analysis (R) was used to assess the association between variables.The differences in categorical data have been statistically assessed using a χ 2 test with its confidence interval (CI).The null hypothesis was rejected at the level of p < 0.05 for all analyses.

Results
The groups differed not only in age parameter (F = 2107.8;р = 0.0000001), but also in body mass (F = 2.5; р = 0.04), and ВMI (F = 4.7; р = 0.001).Additionally, the analysis confirmed the prominent loss of height (F = 14.3; р = 0.0000001) with the age.Scheffe test confirms less parameters of height in the age group 60-69, 70-79 and 80-89 years (p < 0.01 for all groups) compared to the index in women aged 40-49 years.The height of the last two groups was also lower than index in the females aged 50-59 years old.Despite the absence of significant differences in weight between study groups using Scheffe test, BMI in the age group 60-69 years old was higher compared to the indices in females aged 40-49 years old (р = 0.01), 50-59 years old (р = 0.02) and did not differ from the parameter in older subjects.The clinical and anthropometric characteristics of the participants are presented in Table 1.
153 women (26.7 %) had a high risk of sarcopenia (SARC-F ≥ 4 points) in the whole group and the risk of sarcopenia according to the SARC-F questionnaire increased with age.The frequency of a high risk of sarcopenia increased with age (Kruskal-Wallis test: H = 184.6;p < 0.0001), from 1.5 % in the 40-49-year-old group, where it was registered only in one patient, to 73.7 % in the subjects over 80 years old.Among the females older than 70 years, the median was higher than 4 points -the criterion for establishing a high risk of sarcopenia according to SARC-F (Table 2).
Muscle strength according to the grip of the dominant and non-dominant hand changed with age as well.It was the highest in the women aged 40-49 years old, in all other age groups muscle strength was significantly lower.Hand grip strength was lower in each older age group than in the previous one, except for the 50-59 years old and 60-69 years old age groups, which have no differences.The lower time to complete the five-repetition sit-to-stand test was in the persons 40-49 years old and worsened with each decade (Table 2).
The risk of fall (according to Desmond questionnaire) also increased with age (Kruskal-Wallis test: H = 33.6;p < 0.00001).Women aged 50-59 years old have a higher risk than women aged 40-49 years old, and females over 60 years old have a higher one, than women aged 40-49 and 50-59 years old (Fig. 1).The highest risk of fall was established in the age group 80-89 years old; the para meter was higher than in the females 40-79 years old.The sub-  The parameters FRAX as previous ones also were agedependent (Table 3) that confirmed an increase of the frequency of low-trauma fractures from 12.5 % in the age group 40-49 years old to 23 % in the age group 80-89 years.

Parameters
An increase of the risk of sarcopenia, risk of falls, and fractures with age leads to a decrease in independence in everyday life.The percentage of the women who needed assistance (IADL points less than 8) increased from 21.3 % in the women aged 50-59 years old to 81.6 %, in the women aged 80-89 years old.At the next stage, women were divided into 2 groups, depending on the presence of a high risk of sarcopenia.
Due to the significant effect of age on all studied parameters, the groups were standardized by age to determine the effect of the high risk of sarcopenia.The average age of women with a high risk of sarcopenia (group I) was 71.5 ± 8.4 years, and of women without risk (group II)were 71.1 ± 4.5 years (p < 0.05).Subjects of the two groups did not differ as well in BMI: group I (28.4 ± 5.5 kg/m 2 ), group II (27.5 ± 4.6 kg/m 2 , p < 0.05).However, among females with a high risk of sarcopenia, obesity was estab-lished more often -in 63 women (41.1 %) vs. females with SARC-F less than 4 -37 (26.4 %), χ 2 = 10.9 (CI: 5.7-23.3,p < 0.001).
Subjects with a high risk of sarcopenia had a higher risk of falls (according to the Desmond questionnaire) The correlation analysis showed that the risk of sarcopenia according to SARC-F significantly increased with age (R = 0.52, p < 0.0001), as well as the risk of falls according to Desmond (R = 0.23, p < 0.0001).

Discussion
The term "sarcopenia" as a description of generalized age-depended muscle loss was proposed as early as 1998, but its clinical definition and diagnostic criteria were published first time in 2010 [19].Previously, sarcopenia was consi dered as an altered condition of muscles, and the status of the disease was obtained in 2016 and was included in the supplemented 10 th International Classification of Di seases (ICD-10) under code M 62.84.In 2019, an updated EWGSOP2 consensus [3] was published, presenting a modern step-bystep approach to sarcopenia risk, diagnosis, confirmation, and severity.Studies of the prevalence of sarcopenia in the Ukrainian population had been started in 2010-2012 [13].In a cohort study involving 8,637 women aged from 20 to 89 years old, an increase in the proportion of sarcopenia up to 7 % in women at the age over 65 years old was demonstra ted, and if obese persons were excluded, it was up to 10 % [20].Further research by the authors using other sarcopenia criteria revealed a higher proportion of sarcopenia, which was 21.3 % in females older than 65 years Оригінальні дослідження / Original Researches old, from 4.1 in the 50-59-year-old group to 30.8 % in the 80-89-year-old group [21].Different diagnostic criteria used in different studies lead to significant differences in the results.In addition, according to EWGSOP2, the criteria for sarcopenia have changed, for today the main criterion is not muscle mass, as it was considered before, but muscle strength.And although changes in muscle tissue reach clinical significance in elderly persons, their foundation is made at a younger age, when there are still opportunities for preventive influence.Currently, the interconnection between sarcopenia and falls and fractures is continued to be studied and has not been analyzed in the Ukrainian population so far.Therefore, the aim of the study was to study age-related changes in the risk of sarcopenia, falls and fractures in the women in the late reproductive and postmenopausal periods.Nowadays, according to the recommendations of the European and Asian Working Groups on the study of sarcopenia [3,22], despite its moderate sensitivity, SARC-F is an important disease risk tool.According to Malmstrom T.K. et al., SARC-F is a valuable prognostic tool in the need for outside care and correlates with impaired activities of daily living (IADL), reduced gait speed, and reduced hand muscle strength [23].Another widely used questionnaire that has been recommended to be used in individuals in order to predict the risk of low-traumatic fractures related to osteoporosis is the FRAX, which is currently included in a number of international and national recommendations for the management of osteoporosis [24].10-years probability of the low-energy fracture according to FRAX tool, is based on age, BMI, and clinical risk factors (previous fractures, parents' hip fractures and disorders strongly associated with osteoporosis).Contrary, the SARC-F questionnaire assesses fall risk and muscle function, whereas the FRAX does not take this information into account.Although SARC-F and FRAX measure different parameters, their use is interesting, especially in the subjects with high risk of sarcopenia which have a higher fracture and fall risks without age and BMI differences.

Parameters
In our study, it was found that 26.7 % of women at the age over 40 years old have a high risk of sarcopenia, and this index increases from 1.5 % in the subjects at the age 40-49 years old to 73.7 % in the females over 80 years old.In a study by Chinese colleagues, it was shown that among persons older than 60 years old (average age 78.1 ± 7.4 years), 57.7 % had a high risk of sarcopenia [25].In our study, this index was lower (39.3 %), but the average age of our cohort was also lower.
In another study, among the persons with osteoporosis, about 30 % of the patients had a high risk of sarcopenia according to SARC-F, and only 6 % had established sarcopenia, among whom only 3 % had a SARC-F higher than 4 points [26].Currently, the search of screening tools continues, other cut-off points of SARC-F -more than 1, 2 or 3 points are being considered [27][28][29].Despite different rates of prevalence, in all studies the risk of sarcopenia increases with age.
The main factors associated with sarcopenia also include low body weight [25,30].A study conducted in Taiwan showed that a low BMI is one of the leading risk factors for sarcopenia, and its increase by 1 kg/m 2 significantly reduces the sarcopenia risk.Australian scientists proposed to predict appendicular muscle mass using a formula based on age and BMI.Validation of this approach in three cohorts of the patients showed strong correlations between predicted and actual appendicular muscle mass determined by densitometry method [31].The proposed method allows reducing the need of instrumental research, but with this approach, it is impossible to diagnose sarcopenia in the subjects with obesity, the proportion of which was, significantly, higher among the subjects at sarcopenia risk in our study.
According to the similar method, on the basis of age and BMI, the risk of fractures is predicted in the FRAX algorithm.Fractures are the consequences of sarcopenia, but the mechanisms of these connections are currently not fully understood.One of the possible links is a high risk of falls due to muscle weakness, but other pathogenetic connections are also possible.For example, low body mass index and age, which are common risk factors for sarcopenia and osteoporosis, as the main predictor of fractures.However, in our study, the subjects at high risk of sarcopenia did not have low BMI, and the incidence of obesity was even higher than that of women without high risk.The advisability of using the diagnosis of sarcopenia in the subjects at risk of fractures and the choice of the necessary tools for this are currently being actively discussed.According to some studies, SARC-F is a useful screening tool in the diagnosis of sarcopenia in individuals with osteoporosis and hip fractures [32,33] and its use in addition to FRAX improves the informativeness of the last one in predicting of hip fractures [34].According to another study, SARC-F in the patients with osteoporosis has only auxiliary value and is not very informative for the diagnostics of sarcopenia [26].
In our study, women at high risk of sarcopenia also had significantly lower indices of muscle strength (as assessed by a hand dynamometer and a five-repetition sit-to-stand test), which may have an impact on daily activity, and higher IADL questionnaire indices regardless of age.Among wo men who needed external help, 68.8 % had a high risk of sarcopenia.
The relationship between the high risk of sarcopenia (according to SARC-F) and the frequency of falls has been revealed, so the relative risk of falls among the patients with SARC-F > 2 increases by 1.5 times [27,28].In our study, patients at high risk of sarcopenia also had a increased risk of falls regardless of age, but there was no association with the fracture risk determined by the Ukrainian version of FRAX, although women with SARC-F ≥ 4 had a higher fracture rate.In our opinion, FRAX and SARC-F assess different aspects of fracture occurrence.And if the first one predicts the bone state to a greater extent, then the second -the state of the patients' functional capabilities, walking speed, and balancing capabilities [23,29].
The limitations of this study were study design (one center cohort study), population (only females were included).So, multi-center prospective studies are important to investigate the early and long-term relationships between sarcopenia and falls and fractures.

Conclusions
Therefore, women with a high risk of sarcopenia have a higher risk of falls, fractures, and more limitation in daily living activities.
Ключові слова: саркопенія; падіння; переломи Information about authors A. Musiіenko, MD, PhD, Senior Research Fellow at the Department of Clinical Physiology and Pathology of the Musculoskeletal System, State Institution "D.F.Chebotarev Institute of Gerontology of the NAMS Ukraine", Kyiv, Ukraine; http://orcid.org/0000-0002-1672-1991N. Zaverukha, MD, Young Research Fellow at the Department of Clinical Physiology and Pathology of the Musculoskeletal System, State Institution "D.F.Chebotarev Institute of Gerontology of the NAMS Ukraine", Kyiv, Ukraine; http://orcid.org/0000-0002-0181-2794N. Grygorieva, MD, PhD, Professor, Head of the Department of Clinical Physiology and Pathology of the Musculoskeletal System, State Institution "D.F.C hebotarev Institute of Gerontology of the NAMS of Ukraine", Kyiv, Ukraine; e-mail: crystal_ng@ukr.net;http://orcid.org/0000-0002-4266-461XM. Bystrytska, MD, PhD, State Institution "D.F.Chebotarev Institute of Gerontology of the NAMS of Ukraine", Medical Center "Dobrobut-Polyclinic", Kyiv Ukraine; http://orcid.org/0000-0001-7755-1247Conflicts of interests.Authors declare the absence of any conflicts of interests and own financial interest that might be construed to influence the results or interpretation of the manuscript.Information about funding.The study was carried out within the framework of the scientific research of State Institution "D.F.Chebotarev Institute of Gerontology of the National Academy of Medical Sciences of Ukraine" ("Sarcopenia: risk factors, mechanisms, diagnostiсs, prevention and treatment, connection with of the musculoskeletal diseases", No. 0120U102515).The institution that financed the research was the National Academy of Medical Sciences of Ukraine.Authors' contribution.A. Musienko -development of the research concept and design, analysis of the results, writing the text of the article; N. Zaverukha -collection of material, analysis of the results; N. Grygorieva -analysis of the results, editing of the article.M. Bystrytska -analysis of the results, editing of the article.