Mechanistic actions of eldecalcitol and alfacalcidol across the muscle-metabolic axis: A selectivity perspective in sarcopenia and type 2 diabetes

Sarcopenia and type 2 diabetes mellitus (T2DM) share a convergent molecular landscape characterized by chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and impaired insulin-anabolic signaling in skeletal muscle. Although vitamin D receptor (VDR) activation has been implicated in modulating each of these domains, vitamin D analogs are frequently regarded as pharmacologically interchangeable. However, it remains unclear whether structurally distinct VDR ligands may exhibit functional selectivity, generating qualitatively divergent transcriptional and signaling outcomes within the muscle-metabolic axis. In this review, we examine eldecalcitol and alfacalcidol, two clinically approved active vitamin D analogs, as pharmacological models to interrogate ligand-specific VDR signaling. We analyze differences in structural configuration, binding protein affinity, metabolic activation, and receptor engagement dynamics, and evaluate their intersection with three key domains relevant to sarcopenia and T2DM: NF-κB-mediated inflammation, Nrf2-dependent redox regulation, and PI3K/Akt/mTOR-FOXO signaling governing muscle protein turnover. We stratify available evidence into direct skeletal muscle data, systemic and non-muscle findings, and hypothesis-driven integrative models. While preclinical studies suggest context-dependent modulation of inflammatory and anabolic pathways, direct comparative analyses demonstrating ligand-specific VDR transcriptional bias in human skeletal muscle remain lacking. Accordingly, the concept of functional selectivity is presented as a biologically plausible but as yet unproven framework, intended to guide future translational investigations.