Musculoskeletal decay and bone–muscle crosstalk during physical disuse: Mechanisms and integrated countermeasures

Abstract Older adults experience a markedly increased risk of falls and fractures following hospital discharge, largely due to the rapid musculoskeletal deterioration associated with bed rest. Although age‐related muscle and bone loss typically develops gradually, acute physical inactivity accelerates key biological processes underlying sarcopenia and osteoporosis, including muscle atrophy, anabolic resistance, increased bone resorption and reduced mechanical loading. Emerging evidence indicates that muscle, bone and adipose tissue communicate through interconnected biochemical pathways; however, the shared biological mechanisms underlying this crosstalk during acute unloading remain poorly understood. To review the effects of disuse on the muscle–bone–adipose axis, emphasizing disruption of inter‐tissue signalling pathways and evaluating integrated countermeasures, a narrative review was conducted using PubMed, Scopus and Web of Science, focusing on human bed rest and disuse studies, musculoskeletal crosstalk and multimodal interventions involving exercise and nutrition in older adults. Disuse rapidly disrupts musculoskeletal homeostasis by uncoupling bone turnover and inducing muscle anabolic resistance. These changes are accompanied by alterations in myokine and osteokine signalling, including increased myostatin, reduced irisin, elevated RANKL, bone and muscle steatosis, and sclerostin upregulation, further compromising muscle–bone interactions. Evidence supports multimodal interventions combining resistance exercise with optimized protein intake (1.2–1.5 g/kg/day) and nutritional supplements, including β‐hydroxy‐β‐methylbutyrate, vitamin D and creatine, to attenuate muscle and bone loss. Preventing disuse‐related musculoskeletal decline requires recognizing muscle and bone as an integrated functional unit. Tailored multimodal strategies may preserve musculoskeletal health and functional independence in hospitalized older adults, although implementation must consider frailty, comorbidities, safety and feasibility.