Osteosarcopenia as a risk factor for fractures and mortality– 19-year follow-up of a population-based sample

doi:10.21203/rs.3.rs-6662182/v1

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Osteosarcopenia as a risk factor for fractures and mortality– 19-year follow-up of a population-based sample

https://doi.org/10.21203/rs.3.rs-6662182/v1

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published 06 Nov, 2025

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Purpose

This study assessed osteoporosis, sarcopenia and osteosarcopenia as risk factors for fractures and mortality during 19-year follow-up.

Methods

The study population consisted of 2142 individuals aged 55 and older participating in the Finnish population-based Health 2000 Survey. Probable sarcopenia was defined as grip strength below 27 kg for men and below 16 kg for women. Osteoporosis was identified by a bone density T-score below -2,5 via ultrasound or a self-reported diagnosis. Participants were divided into four categories: neither condition, probable sarcopenia only, osteoporosis only, or osteosarcopenia. Fractures and deaths were identified from the national registers until end of 2019.

Results

Over a mean follow-up of 19.1 years, 482 (23%) participants sustained a low-energy fracture of any type and [MN1] 1252 (59%) died. Osteosarcopenia, probable sarcopenia and osteoporosis were all associated with increased risk of any fracture and mortality compared to no sarcopenia no osteoporosis group. Osteoporosis alone was associated with lower mortality than osteosarcopenia (HR 0.69, 95% CI 0.51-0.95), but mortality did not differ between probable sarcopenia and osteosarcopenia (HR 0.80, 95% CI 0.59-1.07). No differences in the fracture risk between osteosarcopenia, sarcopenia and osteoporosis were observed.

Conclusion

While both sarcopenia and osteoporosis significantly increase fracture and mortality risks, their combination does not seem to additively elevate fracture risks. Osteoporosis is a stronger predictor for future fractures, whereas probable sarcopenia is more closely linked to mortality. Further research is warranted to determine the best ways to incorporate sarcopenia assessment into comprehensive fracture risk evaluation

Mini-abstract

Osteoporosis, sarcopenia, and osteosarcopenia were assessed as fracture and mortality risk factors over 19 years in 2,142 adults. All conditions increased fracture and mortality risks. Osteosarcopenia showed no higher fracture risk than sarcopenia or osteoporosis alone but had higher mortality risk compared to osteoporosis alone.

[MN1]any fragility fracture/low-energy fracture?

osteosarcopenia

sarcopenia

osteoporosis

fracture

mortality

risk

older adults

Osteoporosis is a systemic skeletal disorder characterized by low bone mineral density and microarchitectural deterioration of bone tissue, and has long been established as a significant risk factor for fractures, particularly those of the spine, hip, distal forearm and proximal humerus. [1, 2]. Osteoporotic fractures are associated with significant morbidity, reduced quality of life, and increased mortality. [1, 2]

Sarcopenia, an age-related condition characterized by muscle wasting and weakness, has been linked to an increased risk of any fracture, spine fracture and hip fracture. [3–6] Furthermore, sarcopenia is recognized as a risk factor for mortality [7], with the increased risk likely arising from various pathways, including cardiovascular, respiratory, and neurodegenerative diseases. [4] Although sarcopenia is defined by low muscle strength combined with low muscle mass, research indicates that low muscle strength is more strongly associated with morbidity and mortality than low muscle mass alone. [8] A diagnosis of probable sarcopenia is made when an individual exhibits low grip strength, even in the absence of muscle mass measurements. [4]

Both osteoporosis and sarcopenia are known to increase the risk of fractures, and sarcopenia is a risk factor for falls. [3] Therefore, it might be expected that their combination, known as osteosarcopenia, would lead to an even greater fracture risk than either condition alone. Osteosarcopenia is considered a geriatric syndrome that can help identify patients at high risk for fractures and related health issues. [9] A recent meta-analysis suggests that osteosarcopenia increases the risk of falls, fractures, and mortality. [10] This meta-analysis, however, does not give insight into whether osteosarcopenia is a stronger risk factor for these adverse events than sarcopenia or osteoporosis alone.

To the best of our knowledge, only two prospective studies have examined the combined effect of low grip strength or low muscle mass, and low bone mineral density (BMD) on risk of fracture and mortality. Neither of these studies found evidence that osteosarcopenia poses a greater risk for fractures or mortality than sarcopenia or osteoporosis alone [11, 12] However, the study by Scott et al. only included men, and the study by Balogun et al. had limited sample size to conclude whether osteosarcopenia increases the risk more than having sarcopenia or osteoporosis alone in the general population.

This study aimed to compare the risk of any fracture, major osteoporotic fracture, hip fracture and mortality among individuals with probable sarcopenia only, osteoporosis only, osteosarcopenia, and those with neither condition, using a nationwide cohort study representative of the general Finnish population aged 55 and older, with follow-up data spanning up to 19 years.

Study Population

This study utilizes data from the Health 2000 survey, a comprehensive health examination survey conducted across Finland in 2000-2001. A random sample of 10,000 individuals aged 18 and above was drawn from the national population register, employing a stratified two-stage cluster sampling method. The survey included both community-dwelling and institutionalized individuals residing in mainland Finland. Detailed descriptions of the survey's methodology have been published previously [13]. In total, 8,028 participants took part in the survey, with 3,439 of them being 55 years or older. For this study, we focused on participants aged 55 and above who had available data on sarcopenia and osteoporosis, resulting in a sample size of 2,142 (62.3%).

Measurement of probable sarcopenia, osteoporosis and osteosarcopenia

Grip strength was assessed using an electronic device (Good Strength, IGS01, Metitur Oy, Finland) with participants seated and their elbows resting on a table while holding the device's handle. [13, 14] The measurement was conducted twice, with a 30-second interval between attempts. If the difference between the two measurements exceeded 10%, a third measurement was taken. The highest value recorded was used for analysis. Probable sarcopenia was identified based on the EWGSOP2 criteria, with low grip strength defined as less than 27 kg for men and less than 16 kg for women. [4]

Bone mineral density was evaluated using a calcaneal ultrasound device (Sahara Clinical Bone Sonometer, Hologic, Waltham, Massachusetts). The Quantitative Ultrasound Index (QUI), provided by the manufacturer, served as the indicator of bone mineral density. QUI was calculated from the speed of sound (SOS) and broadband ultrasound attenuation (BUA) using formula:

Osteoporosis was defined as a bone density measurement with a T-score less than -2.5, based on ultrasound results. The reference group for the T-score consisted of 30–35-year-old women without chronic illness or disability (n=300). [1] Additionally, participants reporting a prior diagnosis of osteoporosis confirmed by DXA (dual-energy X-ray absorptiometry) were classified as having osteoporosis, regardless of their ultrasound-based bone density measurement. In total, 163 participants (8%) self-reported a prior osteoporosis diagnosis.

Osteosarcopenia was defined as having both probable sarcopenia and osteoporosis. Study participants were assigned into four groups: no sarcopenia and no osteoporosis, probable sarcopenia only, osteoporosis only, and osteosarcopenia.

Measurement of bone fractures

The follow-up information about bone fractures was obtained from the National Hospital Discharge Register by using the national identification numbers assigned to each Finnish resident.

Fractures were identified by the ICD-10 codes corresponding to the care event and three different fracture outcomes were defined: any fracture, major osteoporotic fractures and hip fractures. The following ICD-10 codes and all their sub-codes were included in the ‘any fracture’ outcome: S02, S12, S22, S32, S42, S52, S62, S72, S82, and S92. Major osteoporotic fractures, as defined by the WHO, included hip (S72), clinical spine (S12, S22, S32), shoulder (S42), and wrist fractures (S52). To comply with the WHO’s definition of Major osteoporotic fracture, exclusions were made for non-vertebral thoracic and pelvic fractures (S22.2-S22.9, S32.1-S32.8), non-wrist and non-shoulder upper extremity fractures (S52.0-S52.4, S52.7-S52.9) and diaphyseal and distal femur fractures (S72.3, S72.4, and S72.7-S72.9). [15] Hip fractures included events coded as S72.0, S72.1 and S72.2. Because high-energy impacts may cause fractures regardless of bone health or sarcopenia status, we excluded all fractures resulting from a high-energy impact (traffic accidents, falls down stairs or ladders, injuries from motorized machines).

To exclude participants with earlier bone fractures for sensitivity analysis purposes, information on fractures preceding the enrollment for the study was also gathered from the National Hospital Discharge Register. In total, the data on fractures spanned from November 21^st, 1994, to December 31^st, 2019.

The follow-up for each fracture outcome (any fracture, major osteoporotic fracture, and hip fracture) continued until the occurrence of the specific fracture type being analyzed, the date of death, or the end of the study period (December 31st, 2019), whichever came first. Participants experiencing a different fracture type remained in the study for the outcome of interest.

Mortality ascertainment

Mortality was followed until the date of death or end of follow-up, i.e. 31^st December 2019. The Health 2000 dataset was linked to Statistics Finland’s Causes of Death Register, which includes information on the date and cause of death, by utilizing the personal identity codes assigned to each Finnish resident.

Demographic and lifestyle-related covariates

Information on age and sex were obtained from the population register. Education, smoking, physical activity and mobility limitations were obtained from survey questionnaires. Education was categorized as basic, secondary or higher. Smoking was categorized dichotomously as current and ex-smokers, or never smokers. Physical activity was categorized either exercise training (“Leisure time includes strenuous physical exercise at least 3 hours per week”), active (“Leisure time includes walking, bicycling and other forms of physical activity at least 4 hours per week”) or inactive. (“Leisure time consists of reading, television, or activities not involving physical activity”)[16] To measure mobility, subjects were asked “Are you able to walk about half a kilometre without resting?” and “Are you able to climb one flight of stairs without resting?”. Any difficulty in either task indicated a mobility limitation.

Statistical analysis

Comparisons between osteosarcopenia groups at the baseline were performed using Student’s t test for continuous variables and chi-square test for categorical variables.

To examine the association between osteosarcopenia groups and fracture risk and mortality, we used three different analytic approaches. First, we conducted unadjusted survival analyses using Kaplan-Meier estimates with 95% confidence intervals (PROC LIFETEST in SAS 9.4). Second, we performed multivariable survival analyses using the Cox proportional hazards model (PROC PHREG in SAS 9.4) to estimate adjusted hazard ratios (HR) with 95 % confidence intervals (CI). Initially we adjusted the analyses for age and sex (Model 1). In Model 2 we additionally adjusted for education, smoking, and physical activity; and in Model 3 we additionally adjusted for mobility limitation. Finally, in Model 4, to further account for death as a competing risk for fractures, we utilized the Fine-Gray method incorporating covariates from Model 3. [17] We tested the proportional hazards assumption using Schoenfeld residuals.

We also conducted several sensitivity analysis to test robustness of our findings. First, to eliminate the risk of previous fractures being identified as new incidents, we excluded all subjects with previous fracture of the respective type (e.g. excluded all those with a previous hip fracture from the hip fracture hazard analysis). Second, we included only fractures resulting from low-energy impacts (falls on the same level, falls from bed, falls due to ice and snow) to capture only fractures related to fragility. Finally, we limited the follow-up to December 31^st, 2010, i.e. about 10 years, to minimize the bias related to changing health status and especially changes in the exposure variables. For all sensitivity analyses we used the Fine-Gray method for fractures, and Cox Proportional Hazards analysis for mortality, both with adjustment Model 3.

All analyses were conducted using SAS software version 9.4 (SAS Institute Inc., Cary, North Carolina, United States). The analysis code used for this study is available in the supplementary materials.

The mean age at baseline varied across groups, with the no sarcopenia, no osteoporosis group having the lowest (65.3 years, SD 7.8) and the osteosarcopenia group having the highest mean age (80.4 years, SD 8.6). Large majority of the participants in the osteoporosis only and osteosarcopenia groups were women (90% and 88%). Detailed baseline characteristics across osteosarcopenia groups are shown in Table 1.

During the follow-up 466 participants (21.8 %) sustained a fracture of any type, 321 (15.0 %) a major osteoporotic fracture, 145 (6.8 %) a hip fracture and 1252 (58.5 %) died. Figure 1 presents Kaplan-Meier survival curves for each outcome separately.

Any low-energy fracture

The mean follow-up time to any low-energy fracture occurrence, death or end of follow-up was 11 years. The hazard of any low-energy fracture was higher in probable sarcopenia only (HR 1.56, 95% CI 1.16-2.16), osteoporosis only (HR 2.22, 95% CI 1.67-2.95), and osteosarcopenia groups (HR 2.04, 95% CI 1.33-3.15) compared to the no sarcopenia, no osteoporosis group even after adjusting for demographics, lifestyle factors and mobility limitation (Table 2). When competing risk of death was accounted for, only the osteoporosis only group had a significantly higher hazard (HR 1.99, 95% CI 1.48 - 2.68) compared to the no sarcopenia, no osteoporosis group. Probable sarcopenia only and osteoporosis only groups did not differ from the osteosarcopenia group in terms of hazard for any low-energy fracture (Table 3).

Major osteoporotic fracture

The mean follow-up period for major osteoporotic fracture outcome was 12 years. The hazard for major osteoporotic fracture was significantly higher in probable sarcopenia only, osteoporosis only, and osteosarcopenia groups compared to the no sarcopenia, no osteoporosis group in age and sex adjusted model (Table 2). When further adjusted for demographic and lifestyle factors and additionally for mobility limitation, the osteoporosis only (HR 2.26, 95% CI 1.63-3.14) and osteosarcopenia groups (HR 2.13, 95% CI 1.32 – 3.44) remained at higher hazard compared to the no sarcopenia, no osteoporosis group. When competing risk of death was accounted for, only the osteoporosis only group had a significantly higher hazard compared to the no sarcopenia, no osteoporosis group (HR 2.00, 95% CI 1.39 – 2.87). The hazard of major osteoporotic fracture was not different for osteosarcopenia group when compared to the probable sarcopenia only and osteoporosis only groups (Table 3).

Hip fracture

The mean follow-up period for hip fracture outcome was 12 years. The osteoporosis only and the osteosarcopenia groups had a higher hazard of hip fracture, no osteoporosis group in age and sex adjusted model, whereas the probable sarcopenia only group showed no difference to the no sarcopenia, no osteoporosis group. (Table 2). After adjusting for demographic and lifestyle factors and mobility limitation, only the osteoporosis only (HR 2.15, 95% CI 1.30-3.53) group had a significantly higher hazard of hip fracture compared to the no sarcopenia, no osteoporosis group. This remained statistically significant when accounting for the competing risk of death (HR 1.80, 95%CI 1.02-3.19). There were no differences between the osteosarcopenia group and the probable sarcopenia only or the osteoporosis only groups (Table 3).

Death

The mean follow-up period for mortality was 12 years. Mortality was significantly higher in the probable sarcopenia only (HR 1.56, 95% CI 1.27 – 1.91), osteoporosis only (HR 1.36, 95% CI 1.07 – 1.72) and osteosarcopenia groups (HR 1.96, 95% CI 1.50 – 2.57) compared to the no sarcopenia, no osteoporosis group after adjusting for demographics, lifestyle factors and mobility limitation (Table 2). When compared to the osteosarcopenia group, the osteoporosis only group had significantly lower mortality (HR 0.69, 95% CI 0.51 - 0.95) while mortality in the probable sarcopenia only group did not significantly differ from mortality in the osteosarcopenia group (Table 3).

Sensitivity analyses

The main analyses were repeated including only subjects with no previous fracture of the respective type, including only low energy fractures, and restricting the follow-up period to approximately 10 years. When subjects with previous fractures of the same type were excluded, the osteoporosis only group was no longer statistically significantly different from the no sarcopenia, no osteoporosis group in terms of hip fracture hazard (HR 1.66, 95%CI 0.94-2.91) (Table S1 The same difference to the main results was observed when restricting the analysis to fractures with a confirmed low-energy cause (HR 1.64, 95%CI 0.90–2.98), rather than excluding only those with a known high-energy cause (Table S2).. When restricting the follow-up period to 10 years, the hazard of any fracture was higher in the probable sarcopenia only, compared to the no sarcopenia, no osteoporosis group (HR 1.48, 95% CI 1.01-2.16), which was not observed in the total study population, as well as in the osteoporosis only (HR 1.93, 95% CI 1.31-2.84) and osteosarcopenia (HR 1.87, 95%CI 1.01-2.90) groups compared to the no sarcopenia, no osteoporosis group. Major osteoporotic fracture hazard was higher in osteoporosis only (HR 2.04, 95% CI 1.26-3.31) and also in osteosarcopenia (HR 1.87, 95% CI 1.02 – 3.46), which was not observed in the total study population, compared to the no sarcopenia, no osteoporosis group. For hip fracture, the results were effectively unchanged compared to the main results. Mortality was higher in all groups compared to the no sarcopenia, no osteoporosis group, as was the case in the total study populations. (Table S3)

This population-based study investigated the association of probable sarcopenia, osteoporosis, and osteosarcopenia with the risk of low-energy fractures and mortality. All three conditions were associated with an increased hazard of any low-energy fractures, major osteoporotic fractures, hip fractures and death compared to having neither sarcopenia nor osteoporosis. When comparing the osteoporosis only and sarcopenia only groups to the osteosarcopenic group, no difference in fracture risk was observed. However, the osteoporosis only group had lower mortality compared to the osteosarcopenia group. Thus, while both probable sarcopenia and osteoporosis are risk factors for fractures and mortality, sarcopenia seems to have a somewhat bigger effect on mortality, while osteoporosis has a bigger effect on fracture risk.

Consistent with prior studies [3, 7, 10–12, 18], we found both probable sarcopenia and osteoporosis to be associated with an increased hazard of fractures and mortality (depending on the used statistical model and duration of follow-up). When death was accounted for as a competing risk for fractures, only the osteoporosis only group had an increased hazard of any fracture, major osteoporotic fracture, and hip fracture compared to the no sarcopenia, no osteoporosis group. The difference in results using these two different methods was largely diminished when the follow-up period was reduced from 19 years to 10 years.

This study aimed to elucidate whether osteosarcopenia poses greater risk for fractures and mortality compared to sarcopenia or osteoporosis alone. Our findings corroborate with previous population-based studies from Tasmania by Balogun et al. (2019) and from Australia by Scott et al. (2019)[11, 12]. Balogun et al. found that low grip strength and low bone mineral density measured with DXA increased fracture risk compared to having neither condition, but combined they did not further accentuate the risk. The main difference between our results and the results of Balogun et al. is, that they found no difference in mortality between those with low grip strength regardless of their osteopenia status compared to those with normal grip strength in their multivariable adjusted analysis. [11] The lack of association between low muscle mass or low grip strength and mortality in their findings may be due to the differences in defining low BMD and sarcopenia, chosen covariates in their statistical tests or underpowered sample size. We found osteosarcopenia to be associated with a greater mortality compared to osteoporosis alone. There was, however, no difference between mortality in those with probable sarcopenia alone compared to those with osteosarcopenia suggesting that probable sarcopenia may be more closely linked to mortality than osteoporosis.

Similarly, Scott et al. found that osteopenia/osteoporosis in men was associated with increased fracture risk compared to having neither sarcopenia nor osteopenia/osteoporosis. [12] In addition, those with osteosarcopenia had a similar fracture risk as those with osteopenia/osteoporosis alone. Despite differences in methodologies between these previous studies and our study, they are all in agreement that osteosarcopenia does not seem to increase the risk of fractures above that of either condition alone.

Despite major osteoporotic fractures are known to be caused by low-energy traumas, as indicated by our results as well, the FRAX® tool does not include variables that identify patients in an elevated risk of falls, except for alcohol use.[15] It has been suggested that assessing sarcopenia brings additional value in predicting fracture risk beyond the current version of the FRAX® tool.[6, 19, 20] Sarcopenia is a known risk factor for falls, and physical exercise is an important component of sarcopenia treatment [3, 4]. While no clinical trials have been conducted to conclude the effectiveness of targeted treatment of sarcopenia on reducing falls or fractures, exercise in general substantially reduces falls in those aged 60 and older.[21] It is plausible that those with sarcopenia gain even more benefit from exercise in terms of reducing the risk of falls and subsequent fractures.

Taking the results from Scott et al., Balogun et al., and our study together, identifying individuals with osteosarcopenia has not been shown to be more effective in predicting fracture risk than identifying those with either osteoporosis or low grip strength alone. Based on the evidence currently available, labeling patients as osteosarcopenic may not be particularly useful in fracture risk assessment. However, since both grip strength and BMD are continuously and inversely associated with fracture risk, it is important to measure grip strength in addition to BMD when assessing overall fracture risk.

This study benefits from a large nationwide sample that is representative of the Finnish general population. The National Hospital Discharge Register is reliable and has nationwide coverage. The coverage and quality of the Causes of Death Register kept by Statistics Finland is excellent. The duration of follow-up was exceptionally long, and the number of events of interest was adequate for a well-powered analysis. The methods for assessing bone mineral density and grip strength are well-established.

Nevertheless, some limitations should be recognized. The National Hospital Discharge Register is not fully complete, as fractures that do not require hospitalization may be treated outside hospitals (e.g. local healthcare centers and private clinics). The true number of fractures may thus be higher than presented here. Secondly, while calcaneal ultrasound-based bone densitometry has been shown to predict fracture risk with similar performance to DXA, there are no agreed criteria for diagnosing osteoporosis using calcaneal ultrasound. [22, 23] Lastly, this study lacks appendicular muscle mass assessment, and therefore diagnosis of sarcopenia could not be considered confirmed, but rather probable in those with low grip strength. [4] Consequently, the findings need to be interpreted with caution and further studies on the topic are warranted.

In conclusion, both probable sarcopenia and osteoporosis, as well as osteosarcopenia, were found to increase the risk of low-energy fractures and mortality. However, osteosarcopenia did not appear to pose an additive risk for fractures. On the other hand, osteosarcopenia was found to associate with higher mortality compared to osteoporosis only highlighting the importance of identifying sarcopenia among older adults. Further research is necessary to determine the best ways to incorporate sarcopenia assessment into comprehensive fracture risk evaluation.

Ethics approval

The study protocol of the survey was approved by the Epidemiology Ethics Committee of the Helsinki and Uusimaa Hospital District (407/E3/2000). All participants signed an informed consent before participating in the survey.

Conflict of Interest

M.S.N. has been part of advisory board for Amgen. M.B., K.S., J.P., S.K. and S.S. state no conflicts of interest.

Funding

This work was supported by funding granted by the Research Council of Finland (321625 to K.S.)

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Tables 1 to 3 are available in the Supplementary Files section

No competing interests reported.

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Osteosarcopenia as a risk factor for fractures and mortality– 19-year follow-up of a population-based sample

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Abstract

Figures

Introduction

Methods

Study Population

Measurement of probable sarcopenia, osteoporosis and osteosarcopenia

Measurement of bone fractures

Mortality ascertainment

Demographic and lifestyle-related covariates

Statistical analysis

Results

Any low-energy fracture

Major osteoporotic fracture

Hip fracture

Death

Sensitivity analyses

Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1