Osteosarcopenia increases the risk of mortality: a systematic review and meta-analysis of prospective observational studies

Background & aims Osteosarcopenia is a recently recognized geriatric syndrome. The association between osteosarcopenia and mortality risk is still largely underexplored. In this systematic review with meta-analysis of prospective cohort studies, we aimed to explore whether osteosarcopenia could be associated with a higher mortality risk. Methods Several databases were searched from the inception to 16th February 2024 for prospective cohort studies dealing with osteosarcopenia and mortality. We calculated the mortality risk in osteosarcopenia vs. controls using the most adjusted estimate available and summarized the data as risk ratios (RRs) with their 95% confidence intervals (CIs). A random-effect model was considered for all analyses. Results Among 231 studies initially considered, nine articles were included after exclusions for a total of 14,429 participants (mean age: 70 years; 64.5% females). The weighted prevalence of osteosarcopenia was 12.72%. Over a mean follow-up of 6.6 years and after adjusting for a mean of four covariates, osteosarcopenia was associated with approximately 53% increased risk of mortality (RR: 1.53; 95% CI: 1.28–1.78). After accounting for publication bias, the re-calculated RR was 1.48 (95%CI: 1.23–1.72). The quality of the studies was generally good, as determined by the Newcastle Ottawa Scale. Conclusions Osteosarcopenia was significantly linked with an increased risk of mortality in older people, indicating the need to consider the presence of osteoporosis in patients with sarcopenia, and vice versa, since the combination of these two conditions typical of older people may lead to further complications, such as mortality. Supplementary Information The online version contains supplementary material available at 10.1007/s40520-024-02785-9.


Introduction
Osteosarcopenia is a term derived from "osteo" (bone) and "sarcopenia" (loss of muscle mass and strength) [1].This condition refers to the concurrent presence of osteoporosis and sarcopenia, two age-related musculoskeletal conditions with significant implications for health and functional independence in older adults [1].While osteoporosis and sarcopenia have traditionally been viewed as distinct entities, emerging evidence suggests that they often coexist and share common pathophysiological mechanisms, leading to a synergistic decline in musculoskeletal health [2].
Nowadays, the importance of osteosarcopenia lies in its profound impact on overall health, mobility, and quality of life in older individuals [3].On the one hand, osteoporosis, characterized by low bone mass and microarchitectural deterioration of bone tissue, increases the risk of fragility fractures, particularly in the spine, hip, and wrist, resulting in pain, disability, and loss of independence [4].Sarcopenia, on the other hand, involves the progressive loss of muscle mass, strength, and function, leading to impaired physical performance, increased risk of falls, and functional decline [5].
Probably, the coexistence of osteoporosis and sarcopenia in osteosarcopenia further exacerbates these adverse outcomes, creating a vicious cycle of frailty, disability, and mortality in older adults [6].Individuals with osteosarcopenia are at heightened risk of falls, fractures, hospitalizations, and institutionalization, placing a substantial burden on healthcare systems and society as a whole [7].
Understanding the etiology, epidemiology, and clinical consequences of osteosarcopenia is essential for developing effective prevention and management strategies to optimize musculoskeletal health and promote healthy aging.In this regard, the association between osteosarcopenia and mortality is still underexplored.
Given this background, with this systematic review and meta-analysis of prospective cohort studies, we aimed to explore whether osteosarcopenia could be associated with a higher mortality risk.

Methods
This systematic review and meta-analysis was conducted in accordance with the updated 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [8].The protocol has been registered in Open Science Framework (https://osf.io/5drnu/).

Search strategy
Two independent reviewers (NV and FSR) searched PubMed, Web of Science, and Embase from inception until 16 February 2024.The full search strategy and the search terms used are described in Supplementary Table 1.Discrepancies in the literature search process were resolved by a third investigator (SS).

Inclusion and exclusion criteria
Studies were included based on the following criteria: (i) Baseline data from observational prospective studies; (ii) clear diagnostic criteria for osteosarcopenia indicated as validated criteria for osteoporosis and for sarcopenia; (iii) reporting data regarding mortality and summarizing these data as hazard ratios (HRs) or risk ratios (RRs), deriving from multivariate analyses; and (iv) studies had to include both adults with and without osteosarcopenia.Published articles were excluded if they (i) were reviews, letters, in vivo or in vitro experiments, commentaries, or posters; and (ii) were not published as a full text and in English, since literature has demonstrated excluding such papers has little impact on the effect estimates and conclusions of systematic reviews [9].

Data extraction and risk of bias
Two authors (NV and FSR) extracted data independently, which included name of first author, date of publication, country of origin, participant age, study design, population studied, number of participants, definition of sarcopenia and osteoporosis, tools and criteria for assessing sarcopenia and osteoporosis, follow-up time in years, main condition, number and type of adjustments in statistical analyses.Disagreements between reviewers were resolved by one independent reviewer (SS).
The Newcastle-Ottawa Scale (NOS) was used to assess the study quality/risk of bias [10].The NOS assigns a maximum of 9 points based on three quality parameters: selection, comparability, and outcome.The evaluation was made by two investigator (FSR and NV) and checked by another (SS).The risk of bias was consequently categorized as high (< 5/9 points), moderate (6)(7), or low (8-9) [11].

Outcomes
The outcome of our interest was mortality (overall or specific), reported using any method, including death certificates, medical records, administrative data, or other information, such as asking for information from relatives.

Statistical analysis
The primary analysis compared the cumulative incidence of mortality in patients with osteosarcopenia versus controls, summarizing the data derived from multivariate statistical analyses.In the case of univariate analyses, the number of confounders was posed equal to zero.Then, we calculated the risk ratios (RRs) with their 95% confidence intervals (CIs).Statistical significance was assessed using the random effects model and inverse-variance method [12].
Statistical heterogeneity of outcome measurements between different studies was assessed using the overlap of their confidence interval (95% CI) and expressed as I 2 .Data classification as having low heterogeneity was based on I 2 from 30 to 49%, moderate heterogeneity from 50 to 74%, and high heterogeneity from 75% and above [13].In case of high heterogeneity, a random-effect meta-regression was planned to explore potential sources of variability that could affect estimate rates among studies [14].We plan to consider as moderators mean age of the population, percentage of females, number of adjustments in multivariate analyses (in univariate analyses was posed equal to zero), and follow-up in years, but the main outcome did not suffer on any statistical heterogeneity.
Publication bias was assessed by visually inspecting funnel plots and using the Egger bias test [15].In case of statistically significant publication bias, the trim-and-fill analysis was used [15].For all analyses, a P-value less than 0.05 was considered statistically significant.All analyses were performed using STATA version 14.0 (StataCorp).

Descriptive characteristics
Table 1 shows the main descriptive characteristics of the studies included.Overall, the nine cohort studies included a total of 14,429 participants, followed up for a mean of 6.6 years.They aged a mean of 70 (SD = 6) years, and they were prevalently females (64.5%).The studies were conducted on all continents except for Africa, mainly Asia (n = 4), Europe (n = 2), South America (n = 2), and Oceania (n = 1).Among the main conditions considered, three studies were conducted among community-dwelling older people, while the other six considered specific medical conditions, such as cirrhosis, hip fracture, or similar (see Table 1 for further details).Regarding the diagnosis of sarcopenia, five studies used the criteria proposed by international societies that associated the evaluation of body composition parameters with muscle strength and/or physical performance, one study used phase angle parameters, and the other three  studies, criteria specific for the population examined; similarly, the diagnosis of osteoporosis was made in six studies using a T-score less than − 2.5 SD, while two studies used less than one SD, and one study, criteria specific for the population included (Table 1).
Figure 2 shows the association between osteosarcopenia at the baseline and mortality.After adjusting the analyses for a mean of four potential confounders (see the list in Table 1), the presence of osteosarcopenia significantly increased the risk of mortality in the cohort studies included by 53% (RR = 1.53; 95%CI: 1.28-1.78).This analysis was not affected by any significant heterogeneity (I 2 = 0%), and all the studies reported a significant association between osteosarcopenia and mortality except for one [26].
This outcome was, however, affected by the presence of publication bias (Egger's test p-value < 0.0001): after using the trim-and-fill analysis, with four studies trimmed at the left of the mean, the association was only slightly reduced (RR = 1.48; 95%CI: 1.23-1.72).

Risk of bias
The risk of bias evaluation is reported in Supplementary Table 2. Overall, the mean NOS was 8, with no study at possible high risk of bias.The main source of risk of bias was the short time of follow-up, less than 5 years.

Discussion
In this systematic review with meta-analysis, including nine cohort studies with a total of 14,429 participants followed up for a mean of 6.6 years, we found that the presence of osteosarcopenia at the baseline increased the risk of mortality by 53%, also after accounting for several potential confounders.Even if the outcome suffers from publication bias, the trim-and-fill analysis only slightly attenuated our findings.
The first crucial epidemiological point is the high prevalence of osteosarcopenia found in our meta-analysis, i.e., about 12 of osteosarcopenia significantly affects mortality rate independently from the definition used that was, however, of clinical heterogeneity for both, sarcopenia and osteoporosis.Altogether, our findings suggest that the importance of identifying osteosarcopenia does not stand in the diagnostic criteria used to identify it but in identifying this entity to effectively treat and prevent mortality.
Osteosarcopenia can increase the risk of mortality through different mechanisms.First, and most obviously, osteosarcopenia could increase the risk of fractures, including hip and falls [7,30].Both falls and fractures are widely known risk factors for mortality in older people [31].In this regard, sarcopenia is a progressive and generalized skeletal muscle disorder characterized by the loss of muscle mass and function and is known to be associated with increased adverse outcomes related to fractures, falls, frailty, disability, and mortality [5].Moreover, sarcopenia also represents a significant economic burden worldwide [32], with a remarkable prospected increase in the next 40 years [32].At the same time, osteoporosis is a chronic skeletal disorder characterized by low bone mass and mineral density, along with the deterioration of bone-tissue microarchitecture, further leading to bone fragility and consequential susceptibility to fractures, disability, and mortality [29].With the aging of the global population, these two conditions will become more prevalent, and the incidence of osteosarcopenia will in aging populations.While individual prevalence estimates vary, studies suggest a substantial overlap between osteoporosis and sarcopenia, with prevalence rates ranging from 5 to 20% in older adults [28].Of importance, the prevalence of osteosarcopenia is expected to rise in parallel with the aging population, placing a significant burden on healthcare systems and society [28].Our review, using a meta-analytic approach confirms the epidemiological importance of this entity in geriatrics, across different clinical situations.
Overall, the pooled analysis indicated that osteosarcopenia significantly increased the risk of mortality, and the results were not affected by any heterogeneity, with practically all the studies reporting a significant positive association between osteosarcopenia and mortality.Our findings are in agreement with two previous reviews reporting that osteosarcopenia increased the risk of mortality [7,16].Even if these two systematic reviews increased the risk of our knowledge about this important topic, they could report only three [7] and five studies [16], respectively, therefore having more limited literature compared to our work.Indeed, according to several previous studies, both osteoporosis and sarcopenia individually increased the risk of mortality [5,29].Thus, the possibility that osteosarcopenia could significantly increase the risk of mortality is reasonable, as it involves the co-existence of the two aforementioned conditions [7].Of importance is that the presence Fig. 2 Meta-analysis of osteosarcopenia as predictor factor for mortality 1 3 if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/.thus increase dramatically in the upcoming decades [7].Therefore, osteosarcopenia represents an important public health issue to which great attention should be paid globally, also because it significantly increases the risk of death independently from potential confounders.
The findings of this systematic review must be considered within its limitations.First, we could not estimate whether the risk of mortality caused by osteosarcopenia was higher compared to the presence of sarcopenia or osteoporosis alone due to insufficient original data.Second, even if the I 2 was < 50%, the diagnostic criteria for osteosarcopenia may have affected the results from a clinical point of view, not leading to a univocal definition of this entity.For example, some studies included osteoporotic patients, but others involved osteopenic participants; similarly, sarcopenia was defined according to different criteria.Third, some studies explored osteosarcopenia among community dwellers, while others analyzed specific populations.Fourth, even if we used the results of multivariable analyses, the adjustment factors differed among studies.
In conclusion, our systematic review suggests that osteosarcopenia significantly increases the risk of mortality by about 53% compared to controls.Our results underline the need to consider the presence of osteoporosis in sarcopenic patients, and vice versa, since the combination of these two conditions, typical of older people, may lead to further adverse complications, such as mortality.

Fig. 1
Fig. 1 Prevalence of osteosarcopenia in the studies included .7%.Osteosarcopenia represents a growing concern