Sclerostin regulates bone formation by inhibiting Wnt pathway signaling. Low 
circulating sclerostin levels cause high bone mass. We hypothesized that 
postmenopausal women with increased sclerostin levels have a greater risk for 
osteoporosis-related fractures. We examined the association between circulating 
sclerostin together with bone turnover markers and osteoporosis-related fracture 
risk in 707 postmenopausal women, in a population-based study with a mean 
follow-up period of 5.2 ± 1.3 years. Multivariate Cox proportional hazards 
regression models were used to analyze fracture risk, adjusted for age, body 
mass index, and other confounding risk factors. High sclerostin levels were 
strongly associated with increased fracture risk. After adjustment for age and 
other confounders, the relative fracture risk was more than sevenfold among 
postmenopausal women for each 1-SD increment increase in sclerostin level. Women 
in the highest quartile of sclerostin levels had about a 15-fold increase in 
fracture risk. Results were similar when we compared sclerostin at the 1-year 
visit to an average of two to three annual measurements. Fracture risk 
attributable to sclerostin levels was 56.6% in the highest quartile. Only high 
levels of bone resorption markers (plasma cross-linked C-terminal telopeptide of 
type 1 collagen [p-CTx], urinary CTx [u-CTx], and urinary N-telopeptide of type 
1 collagen [u-NTx]) were predictive of osteoporosis-related fractures but at 
much lower hazard ratio (HR) values than that of serum sclerostin. Associations 
between sclerostin levels and fracture risk were independent of bone mineral 
density and other confounding risk factors. High sclerostin levels are a strong 
and independent risk factor for osteoporosis-related fractures among 
postmenopausal women. © 2012 American Society for Bone and Mineral Research.