The Wnt/β-catenin signaling pathway plays an essential role in osteoblast 
biology. Sclerostin is a soluble antagonist of Wnt/β-catenin signaling secreted 
primarily by osteocytes. Current evidence indicates that sclerostin likely 
functions as a local/paracrine regulator of bone metabolism rather than as an 
endocrine hormone. Nonetheless, circulating sclerostin levels in humans often 
reflect changes in the bone microenvironment, although there may be exceptions 
to this observation. Using existing assays, circulating sclerostin levels have 
been shown to be altered in response to both hormonal stimuli and across a 
variety of normal physiological and pathophysiological conditions. In both 
rodents and humans, parathyroid hormone provided either intermittently or 
continuously suppresses sclerostin levels. Likewise, most evidence from both 
human and animal studies supports a suppressive effect of estrogen on sclerostin 
levels. Efforts to examine non-hormonal/systemic regulation of sclerostin have 
in general shown less consistent findings or have provided associations rather 
than direct interventional information, with the exception of mechanosensory 
studies which have consistently demonstrated increased sclerostin levels with 
skeletal unloading, and conversely decreases in sclerostin with enhanced 
skeletal loading. Herein, we will review the existent literature on both 
hormonal and non-hormonal/systemic factors which have been studied for their 
impact on sclerostin regulation.