Muscle acts as the body’s second heart, is crucial for bone health, consumes blood glucose, and is vital in human metabolism. Middle-aged people lose 3% of their muscle strength and 1% of their muscle mass each year on average (1). Skeletal muscle loss is about 30% at the age of 60 years and about 50% at the age of 80 years (1). Muscle attenuation is usually associated with imbalance between muscle catabolism and anabolism. With increasing age, the body resists normal growth signals, resulting in increased catabolism, which in turn leads to muscle loss and sarcopenia (2). Sarcopenia is a disease characterized by the decline in muscle mass, strength, and function with age (3). This condition may have detrimental effects on the health of older individuals, including an increased risk of falls, fractures, obesity, hypertension, diabetes, and cardiovascular diseases (4–6). The prevalence of sarcopenia in the elderly ≥ 65 years has been reported to be 20% in the Western population, and it reaches 50–60% in those aged ≥ 80 years (7). China has the largest elderly population, and the prevalence of sarcopenia among the community-dwelling elderly is also as high as 12% (8). Growing evidence suggests that sarcopenia is associated with adverse consequences and an increased medical burden (9). It can serve as a predictor for infection risk, length of hospital stay, readmission, hospital complications, decreased physical function, and mortality (10, 11). Consequently, there has been a growing interest in research on the prevention and treatment of sarcopenia in recent years.

HMB, an in vivo metabolite of leucine, has shown potential for improving muscle protein turnover. It is considered the most important regulator of muscle protein anabolism and has been found to promote muscle protein synthesis and inhibit muscle protein decomposition (12). Thus, HMB may be important for preventing muscle degradation in aging populations. Studies have demonstrated that HMB supplementation can improve muscle function, prevent muscle atrophy, promote wound healing, and enhance muscle mass and strength (12–14). Several studies have reported that HMB supplementation has a positive effect on muscle mass, strength, and physical function in the elderly (15–17). Considering the potential of HMB, understanding its role and optimizing its application in the treatment of sarcopenia are important. However, most previous studies have focused on elderly individuals > 65 years. Thus, there is a lack of research involving people aged between 50 and 65 years. After age 50, skeletal muscle mass and muscle strength gradually decrease; specifically, the leg muscle mass decreases by 1–2% per year and muscle strength decreases by 1.5–5% per year (18). Previous studies suggest that the long-term effect of supplementation is beneficial (19, 20). To ensure the safety of participants, the recommended supplement dosage is typically ≤ 3 g/day. However, studies on humans report no side effects with dosages as high as 6 g/day for up to 1 month (16, 21, 22). Thus, the specific role and dosage–duration response relationship of HMB in people > 50 years remain unclear. To provide clear dosage and duration guidance for HMB supplementation, a meta-analysis of the dosage–duration response relationship is warranted. This study focused on participants over the age of 50 and referred to the 2021 Chinese expert consensus on the diagnosis and treatment of sarcopenia in the elderly and the Asia Working Group for Sarcopenia (AWGS) consensus (23, 24) to identify the most clinically relevant evaluation indexes. We selected the appendicular skeletal muscle mass (ASMM) and lean mass (LM) as the evaluation indexes for muscle mass, handgrip strength and the five-time chair stand test as the evaluation indexes for muscle strength, and gait speed and the 6-min walk test (6MWT) as the evaluation indexes for physical function. Using meta-analysis, the effects of HMB oral supplementation on muscle mass, strength, and physical function were first analyzed. Furthermore, the effects of different dosage and duration of HMB oral supplementation on muscle-related indicators were explored. The optimal dosage-duration response relationship was obtained. The aim of the study was to provide evidence for the prevention and treatment of clinical sarcopenia.

This review was carried out in accordance with a protocol registered on PROSPERO (CRD: 42024518958). The method and results are reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines (25) A compiled PRISMA checklist is included in Supplementary material.

The previous meta-analysis explored the effect of HMB supplementation on muscle-related indicators in the population aged 65 and above, with less discussion on the supplementation dosage and duration. However, the age range of 50-65 is a critical period for preventing muscle loss. In this meta-analysis, we included studies on participants over the age of 50, and further investigated the effects of the supplementation dosage and duration, which are two key features of this study. The objective of this meta-analysis was to explore the effects of HMB oral supplementation on muscle mass, strength, physical function, and the dosage–duration response relationship, aiming to provide a scientific basis for the prevention and treatment of clinical sarcopenia. Data analyzed by summarizing all the RCTs meeting the inclusion criteria makes the results more comprehensive than using data from a single study, thereby enhancing the credibility of the findings. The results of the meta-analysis revealed that ASMM and LM were significantly higher in the intervention group than those of the control group, and the combined exercise intervention was more effective, indicating that HMB supplementation has a positive effect on muscle mass, and the combined exercise effect is better. These findings are consistent with those of previous studies. In this regard, Bear et al. (15) reported that HMB supplements have increased muscle mass across various clinical conditions. Wu et al. (50), in their meta-analysis, found that HMB supplementation is involved in preserving muscle mass among older adults and may be useful in the prevention of muscle atrophy. In addition, Molfino et al. (51) and Later et al. (22) concluded that HMB can mitigate exercise-induced muscle damage, further asserting that resistance training (RET) in conjunction with HMB supplementation significantly increases both muscle mass and strength. The underlying rationale for these results may be attributed to HMB’s capacity to inhibit protein breakdown, thereby reducing muscle degradation. In addition, HMB has been associated with increased endoplasmic reticulum calcium release, reduced fat content in skeletal muscle, increased oxygen metabolism, and the activation of satellite cells, consequently promoting muscle regeneration (16, 52, 53). We also considered the two indexes of muscle cross-sectional area and muscle volume. The results showed that HMB supplementation could significantly improve muscle cross-sectional area and muscle density (41, 46). However, because of the limited literature, we did not conduct a meta-analysis.

Several studies have investigated the impact of HMB on muscle strength. These supplements have been found to improve muscle strength in a variety of patients with decreased muscle mass and strength (15). In addition, meta-analyses have consistently demonstrated that HMB preparations can enhance upper and lower-limb muscle strength in the older adults (54, 55). Zhang et al. (56) and Zuo et al. (57) reported that combining HMB supplementation with RET can significantly boost lower-limb muscle strength in older individuals. Consistent with previous findings, the intervention group in our study exhibited significantly better results in handgrip strength and the five-time chair stand test than the control group, and the combined exercise intervention was more effective, indicating the positive impact of HMB oral supplementation on muscle strength, and it is best to combine exercise together. Contrary to these findings, a recent meta-analysis revealed that HMB supplementation had no substantial effect on muscle strength in adults aged 18–45 years (58). Our study, focused on adults > 50 years, contradicts this conclusion by revealing a positive regulatory effect of HMB supplementation on muscle strength in this age group. This reinforces the notion that the optimal population for HMB supplementation is middle-aged and older individuals. However, literature related to handgrip strength and the five-time chair stand test may have risk of bias, necessitating further research for confirmation in subsequent analyses.

Previous research has indicated that the combination of HMB and physical exercise can improve physical function. Li et al. (59) concluded that HMB combined with RET has a positive effect on physical function. In addition, a previous systematic review reported that HMB can improve physical function in older patients with sarcopenia or physical weakness (59). Consistent with these findings, our study also identified that HMB could improve physical function, with the experimental group demonstrating significantly better gait speed than the control group, especially in the case of combined intervention with exercise, the effect is more obvious. This reaffirms the beneficial effect of HMB supplementation on physical function. And this meta-analysis shows that the effect of HMB supplementation on 6MWT is not significant. This is inconsistent with the result of gait speed, although previous meta-analyses have found limited effects of HMB supplementation on physical function, such as Javier (55) found that HMB supplementation alone has limited or no effect on physical function in adults aged 50–80. But we should note that this result is only a combination of three studies, and the grading evaluation shows that 6MWT is very low quality evidence. And this is contrary to the previous study by Wu (60), who found that HMB combined with RET significantly affects the 6MWT of intensive care unit patients. We proposed three potential explanations for this discrepancy. Firstly, there may be a difference in intervention measures, since the RCTs we included in the 6MWT index were HMB supplementation alone, whereas Wu et al. study included RCTs of both HMB supplementation alone and HMB supplementation combined with physical exercise. Secondly, the research subjects are different. We did not limit the health status of the subjects, but Wu et al.’s were ICU patients, and the 6MWT index may be more suitable for evaluating this population. Thirdly, the 6MWT-related literature is very limited and grading assessment rated it as very low quality evidence. Based on comprehensive analysis, we believe that HMB supplementation has beneficial effects on physical function, but further research is needed to confirm these findings in the subsequent analysis.

Subgroup analysis showed that health status, gender and BMI had little effect on the supplemental effect of HMB. Although the results of LM, handgrip strength, gait speed and 6MWT indicate that gender and BMI have a slight impact on the effectiveness of HMB supplementation, the prominent results need further validation as the subgroups with prominent effects often involved only one RCT. After comprehensive analysis, we still believe that health status, gender and BMI are not the interfering factors of HMB supplemental effect. Age, supplementary frequency and whether combined with exercise intervention will affect the effectiveness of HMB. For LM and five-time chair stand test, HMB supplementation has an effect on the population over 50 years old, but the effect is more significant in the population over 65 years old. In this regard, we speculate that it may be caused by the disparity in sample size between subgroups. For LM, there were only two RCTs with subjects over 50 years and under 65 years, involving 67 subjects, and the other 670 subjects belonged to the subgroup of ≥ 65 years old. The gap in sample size between the two age groups may lead to the differences in the effect of HMB. Moreover, the five-time chair stand test may be more inclined to evaluate the elderly population, so it is expected that the effect of HMB supplementation will have a more prominent impact on people aged ≥ 65 years. For LM, handgrip strength and gait speed, supplement frequency once a day is more effective, and the effect of combined exercise intervention is better. Previous studies have also shown that HMB combined exercise can significantly improve muscle mass and strength (22, 51, 56, 57). Subgroup analysis also found that for LM, the effect of HMB oral supplements alone is more effective than that of combined with other substrates. Although the reason is not yet clear, we preliminarily believe that HMB supplementation alone may be more beneficial to LM.

The subgroup analysis revealed a significantly better effect of HMB supplementation at a dosage of 3 g/day than < 3 g/day. In this regard, Nissen et al. (21) studied the HMB supplementary dosage for the first time and found that a dosage of 3 g/day was more effective than 1.5 g/day. However, for participant safety, the majority of studies have maintained HMB dosage in the intervention group at ≤ 3 g/day, resulting in a notable gap in the investigation of dosage > 3 g/day. In this meta-analysis, only one study employed a supplemental dosage > 3 g/day, explicitly indicating that HMB supplementation could enhance muscle mass and physical function in elderly patients with hip fractures and prevent the occurrence of sarcopenia. At present, studies have shown that HMB is a relatively safe nutritional supplement. Animal experiments have shown no significant side effects of HMB, even at high dosages of 100 g/day for 4 days (16). Similarly, human studies demonstrated no side effects with dosages as high as 6 g/day for up to 1 month (16). Consequently, there is a compelling need for researchers to expand their investigations into the effects of supplementation with dosage of > 3 g/day. In addition, more recent studies are warranted to comprehensively evaluate HMB supplementation’s efficacy.

In addition, this meta-analysis revealed that an HMB supplementation duration > 12 weeks had a better effect than a duration ≤ 12 weeks. Several studies have demonstrated that supplementation duration ≤ 6 weeks show no significant difference between the control and placebo groups, whereas supplementation duration > 6 weeks positively impact muscle strength (19, 20, 61–63). Nissen et al. (21) and Wilson et al. (64) reported that HMB supplementation for > 2 weeks results in a more pronounced reduction in protein decomposition and skeletal muscle damage compared with supplementation for only 1 week. Slater and Jenkins (22) found that in the context of long-term endurance training, HMB can mitigate muscle protein degradation and muscle damage, resulting in increased muscle mass and strength, although its impact is less significant in short-term training. This is consistent with our research findings, suggesting that a longer supplementation duration may yield a better effect.

This meta-analysis conducted a subgroup analysis of the combined effects of dosage and duration. For LM and handgrip strength, there are complete data for the four subgroups. The analysis results showed that 3 g/d and > 12 weeks were the best, which is better than subgroup analysis based solely on dosage and duration. The results of ASMM and five-time chair stand test showed that the effect of subgroup 3 g/d and ≤ 12 weeks is significant, but we don’t have the relevant data of longer duration of this dosage, so we cannot confirm whether the effect of 3 g/d and > 12 weeks is more significant. For gait speed, the effect of < 3 g/d and ≤ 12 weeks is already significant, but due to the lack of data for 3 g/d and > 12 weeks, it cannot be confirmed whether the dosage-duration response relationship is more significant. LM and handgrip strength are two key indicators for evaluating muscle mass and strength, and the data for each subgroup is complete. Therefore, the subgroup analysis results of the dosage-duration response relationship between these two indicators are more reliable. In summary, we believe that 3 g/d and > 12 weeks may be the optimal dosage-duration response relationship for HMB supplementation.

This meta-analysis has several acknowledged advantages. First of all, compared to most previous meta-analyses, this meta-analysis added the study on the 50–65 age group and obtained positive research results. Secondly, this meta-analysis added subgroup analysis of dosage, duration, and dosage-duration response relationships, and concluded that HMB is suitable for high-dosage and long-duration supplementation. Thirdly, this meta-analysis conducted subgroup analysis and discussion on parameters that may affect muscle indicators, such as health status, age, gender, BMI, frequency, combination with exercise, and combination with other substances. Last but not least, in order to evaluate the degree of certainty of outcome evidence, this study used the GRADE method to assess the level of evidence.

However, when interpreting our research results, some limitations should be considered. First of all, there is little literature on participants between 50 and 65 years old. Only 4 studies are in this age group, and the rest are all over 65 years old (39, 42, 48, 49). This makes the meta-analysis of ASMM and gait speed only involved objects over 65 years old. And for five-time chair stand test, only one study was between 50 and 65 years old. The results of these three indicators may be more inclined to the elderly population. Even so, our analysis found a promising intervention effect of this age group on other indicators, such as LM and handgrip strength. These two indicators are important for directly evaluating muscle mass and strength. It is worth noting that GRADE assessment shows handgrip strength and 6MWT are very low quality evidence. The results of these two indicators should be further verified in the future. Secondly, five-time chair stand test may have some risk of bias and should be carefully considered. Thirdly, the included studies used various indicator measurement techniques that may provide different results, making it difficult to compare datasets. However, all RCTs used standard protocols and high-quality equipment, so we believe that the differences in measurement techniques between the studies may have a minor impact on the results. Fourthly, subgroup analysis of important parameters of some indicators cannot be performed due to the lack of research data. Therefore, it is necessary to supplement more high-quality RCTs in subsequent studies.

Oral supplementation of HMB can improve muscle mass, strength and body function. Positive effects on muscle mass and strength have been observed in the population aged 50–65. We recommend to implement supplementation at a dosage of no less than 3 g for more than 12 weeks to achieve optimal benefits. This meta-analysis added the study of dosage, duration, and dosage-duration response relationships. The results of this study will provide a reference for the dosage and duration of clinical HMB supplement, and provide a basis for the prevention and treatment of clinical sarcopenia. However, oral supplementation of HMB may also have some potential effects in practical applications, such as whether it will cause gastrointestinal problems, whether it will increase the burden on the liver, and whether it has an effect on hormone levels, which still needs to be further verified in future studies. In addition, due to limited number of studies included and the risk of bias, more studies, especially high-quality RCTs, are needed to further evaluate or confirm the beneficial effects of HMB on muscle strength and physical function.