Bone mineral density, muscle mass and physical function reach their peak between the second and fourth decade of life and then decline steadily with aging. The crucial question is: what factors contribute to or modulate this decline? The aim of this mini-review is to propose a theoretical framework for the potential role of emerging biomarkers such as klotho, fibroblast growth factors (FGF)21 and FGF23 on musculoskeletal health, with a particular focus on decline in muscle mass and function, and calls for future research to examine this proposed link. The identification of new physiological mechanisms underlying these declines may open a potentially important avenue for the development of novel intervention strategies aimed at preventing or reducing their potentially detrimental consequences.