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Dr. Joseph  Lorenzo

Serum Sclerostin Measurements and the Risk of Fractures

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Wnt proteins and the canonical Wnt signaling pathway are now known to play a critical role in the development of the skeleton. Studies over the last 15 to 20 years have demonstrated that mutations in human low-density lipoprotein (LDL) receptor-related protein (LRP) 5, which is a component of the canonical Wnt receptor, are associated with altered bone mass (1, 2) . In addition, two human diseases of high bone mass, sclerosteosis (3) and Van Buchem disease (4) result from mutations in the SOST gene, which produces a protein, sclerostin, that interferes with Wnt signaling. These latter two conditions are characterized by little to no sclerostin production and a phenotype of high bone mass. Because of these findings, a number of pharmaceutical companies are actively engaged in developing anti-sclerostin therapies to increase bone mass and treat diseases like osteoporosis.

 

Sclerostin is predominantly produced in osteocytes and mechanical force on bone critically regulates its production (5, 6). In areas of high force, sclerostin levels rapidly decrease, which, in turn, increases Wnt signaling and enhances bone mass in response to loading. Hence, one function of the “mechanostat” in bone is to regulate sclerostin production. Parathyroid hormone (PTH) is also a potent inhibitor of sclerostin production (7) and this effect may mediate some of the anabolic effects of intermittent PTH administration.

 

Studies of the role of sclerostin in bone have recently been greatly aided by the development of immunoassays that accurately measure serum sclerostin levels. These have demonstrated that sclerostin circulates and its levels are inhibited by treatment with either estrogens or PTH (8). Data from a large population study have also shown that serum sclerostin levels increase with age, are greater in men than in women and negatively correlate with both serum 25 OH vitamin D levels and bone mass (9, 10).

 

Arasu et al (11) have now published a study that examines whether measurement of serum sclerostin correlates with the risk of hip fracture in postmenopausal Caucasian women. These authors reexamined data from a large study at the University of Minnesota that was begun in 1986. Women enrolled in the study were followed for an average of 9.8 years for the development of osteoporotic fractures. In a randomly selected group of 227 women who had banked serum samples from which sclerostin levels could be measured, it was demonstrated that bone mass at the hip, femoral neck and lumbar spine was significantly greater in the quartile with the highest serum sclerostin levels. However, after adjusting for age, BMI, estrogen use, a history of fractures after 50 and total hip BMD, there was a significant trend (p

 

Certainly, these results are intriguing. It is unknown why serum sclerostin levels correlated positively with bone mass in this group since, in cross sectional studies over a wider range of ages, the opposite appears to be true (10). The authors speculate that serum sclerostin levels in this group may reflect the number of osteocytes in individuals. Regardless, the finding in multivariate analysis that serum sclerostin levels have a predictive value for fractures is provocative. Clearly, additional studies are needed. However, should these results be confirmed, serum sclerostin measurements could become a useful clinical index, in addition to BMD, which will help to determine which women need to be treated to prevent future fractures.

 

Joe Lorenzo,

Farmington, CT, USA

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