Mendel (1992) defined the free hormone hypothesis (FHH): the biological activity of a given hormone is ultimately affected by its unbound (free) rather than protein-bound concentration in the plasma1. He believed this hypothesis is likely to be valid with respect to thyroid hormones, cortisol and hydroxylated metabolites of vitamin D.
Almost all circulating 25-OH Vitamin D in serum is bound to VDBP. In addition to VDBP, vitamin D metabolites can bind to albumin or circulate in a free form. Less than 1% of Total 25-OH Vitamin D circulates in the free, non-protein bound form. Chun and Hewison surmised that binding 25-OHVD to VDBP impairs the delivery of 25-OHVD to its target tissues, ultimately preventing metabolism into the active form, 1,25DHVD2. Conversely, it is the unbound, free form that can cross the cell membrane and have a biological action.