Comparative effectiveness of protein or protein-related supplementation combined with resistance or functional...

Resistance and functional exercise are core non-pharmacological strategies for sarcopenia management. Protein or protein-related supplementation is commonly used to support exercise-induced adaptations, but the comparative effects of different supplementation strategies when added to exercise remain unclear.

This systematic review and network meta-analysis compared the additional effects of different protein or protein-related supplementation strategies combined with resistance or functional exercise on grip strength, appendicular skeletal muscle mass index (ASMI), and timed up-and-go (TUG) performance in older adults with sarcopenia or at high risk of sarcopenia.

PubMed, Embase, Cochrane Library, Web of Science, CNKI, and SinoMed were searched from inception to March 16, 2026. Randomized controlled trials comparing exercise plus protein or protein-related supplementation with the same or comparable exercise program plus placebo, no additional supplementation, or exercise alone were included. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. Pairwise and frequentist network meta-analyses were conducted, and intervention rankings were assessed using the surface under the cumulative ranking curve (SUCRA).

Eighteen randomized controlled trials involving 1,341 participants and 12 combined intervention strategies were included. Pairwise meta-analysis showed that supplementation added to exercise significantly improved grip strength (SMD = 0.39, 95% CI: 0.20 to 0.58) and ASMI (SMD = 0.18, 95% CI: 0.00 to 0.35), but not timed up-and-go (TUG) performance (SMD = -0.39, 95% CI: -0.96 to 0.18). For TUG performance, negative SMD values indicate beneficial effects because lower TUG values represent better mobility. Network meta-analysis suggested potential outcome-specific effects of several supplementation strategies, including β-hydroxy-β-methylbutyrate (HMB)-based supplementation, whey- or leucine-enriched protein supplementation, and whey protein/essential amino acids combined with vitamin D strategies for grip strength, and whey- or leucine-enriched protein supplementation for ASMI. The combination of whey protein/essential amino acids and vitamin D with functional exercise showed a potential improvement in TUG performance; however, this finding was based on limited evidence and may largely reflect the contribution of functional exercise components. However, given the sparse evidence network and very low certainty of evidence, intervention rankings should be considered exploratory rather than definitive.

Adding protein or protein-related supplementation to resistance or functional exercise may improve muscle strength and ASMI in older adults with sarcopenia or at high risk. HMB-, whey protein-, or leucine-based strategies showed potential benefits for specific outcomes; however, given the very low certainty of evidence and sparse comparative networks, no single supplementation strategy can be considered definitively superior.

PROSPERO, CRD420261396976.