Association of Serum Sclerostin with Bone Sclerostin in Chronic Kidney Disease is Lost in Glucocorticoid Treated Patients

Abstract

The osteocytic protein sclerostin inhibits bone turnover. Serum sclerostin rises early in chronic kidney disease (CKD), but if this reflects osteocyte sclerostin production is unclear, since sclerostin is also expressed in extra-skeletal tissue. Glucocorticoid treatment impacts on serum sclerostin, but the effect on the association between serum and bone sclerostin is unknown. We sought to determine whether serum sclerostin reflects bone sclerostin in different CKD stages and how this association is influenced by glucocorticoid treatment. In a cross-sectional analysis, we investigated serum sclerostin, bone sclerostin by immunohistochemistry, and bone histomorphometry in iliac crest bone biopsies from 43 patients with CKD 3-5D, including 14 dialysis patients and 22 transplanted patients (18 kidney, 4 other). Thirty-one patients were on glucocorticoid treatment at time of biopsy. Patients with low bone turnover (bone formation rate < 97 µm²/mm²/day; N = 13) had higher median serum sclerostin levels (224.7 vs. 141.7 pg/ml; P = 0.004) and higher bone sclerostin, expressed as sclerostin positive osteocytes per bone area (12.1 vs. 5.0 Scl+ osteocytes/B.Ar; P = 0.008), than patients with non-low bone turnover (N = 28). In linear regression analyses, correcting for age, gender, dialysis status and PTH, serum sclerostin was only associated with bone sclerostin in patients not treated with glucocorticoids (r 2 = 0.6, P = 0.018). For the first time, we describe that female CKD patients have higher median bone sclerostin than males (11.7 vs. 5.7 Scl+ osteocytes/B.Ar, P = 0.046), despite similar serum sclerostin levels and bone histo-morphometric parameters. We conclude that glucocorticoid treatment appears to disrupt the association of serum sclerostin with bone sclerostin in CKD.

Elevated glucose acts directly on osteocytes to increase sclerostin expression in diabetes

“…This suggests that measuring serum sclerostin in diabetic patients may not be the most reliable method in evaluating biological sclerostin activity and bone quality. It has recently been shown that in chronic kidney disease (CKD) patients treated with glucocorticoids, serum sclerostin levels are not associated with bone sclerostin, as assessed by immunohistochemistry 29 . Furthermore, similar to our observations in diabetic animals, bone SOST mRNA and sclerostin protein levels are increased in patients following a kidney transplant, but serum sclerostin levels are decreased 30 .…”

Parathyroid Hormone: A Uremic Toxin

“…This resistance is not restricted to the effects of PTH on calcium release from the skeleton, but also involves the action of the hormone on the response of the bone cells [31]. We and others have shown increased bone expression of sclerostin in CKD patients [32,33], suggesting that this Wnt pathway inhibitor is related to the bone resistance to PTH. As a consequence, high serum PTH levels are needed to induce equivalent biologic responses in patients with CKD.…”

Could Bone Biomarkers Predict Bone Turnover after Kidney Transplantation?—A Proof-of-Concept Study

“…Another important hypothesis is the glucocorticoid treatment used in KT, which appears to initially suppress serum sclerostin levels, but prolonged treatment appears to be associated with increased serum sclerostin levels [35]. In fact, there seems to be a disconnection between bone sclerostin and circulating sclerostin levels, caused by glucocorticoids [36,37]. Sustained increase in plasma levels of bioactive sclerostin after KT, occurs in parallel with the reduction of PTH, although we did not find a significant correlation between sclerostin and PTH, possibly due to small sample size.…”