Sclerostin and Dickkopf-1 in Renal Osteodystrophy

Cejka, Daniel; Herberth, Johann; Branscum, Adam J.; Fardo, David W.; Monier‐Faugere, Marie‐Claude; Diarra, Danielle; Haas, Martin; Malluche, Hartmut H.

doi:10.2215/cjn.06550810

Cited by 225 publications

(219 citation statements)

References 30 publications

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“…This finding is in agreement with results in non-CKD animals and patients showing lower bone formation with higher sclerostin levels (16,17,32). Also, in prior studies in CKD-5D patients, we found a strong negative correlation between sclerostin blood levels and bone formation parameters (38), which could explain why, prospectively, patients with CKD-5D and higher sclerostin lose more bone than patients with lower sclerostin levels. The baseline finding of a positive relationship between sclerostin and baseline BMD in CKD- Figure 1.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

Bone Mineral Density and Serum Biochemical Predictors of Bone Loss in Patients with CKD on Dialysis

Malluche¹,

Davenport

Cantor³

et al. 2014

Clinical Journal of the American Society of Nephrology

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122

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Background and objectives Use of bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA) is controversial for diagnosing bone loss in CKD patients on dialysis. The alternative quantitative computed tomography (QCT) is expensive and requires high radiation exposure. This study compared the two techniques and evaluated serum biochemical parameters for prediction of bone loss.Design, setting, participants, & measurements This prospective study enrolled patients from dialysis centers throughout Kentucky. BMD of the spine and hip was measured at baseline and after 1 year by DXA and QCT. Customary and novel serum biochemical parameters were obtained at the same times, including calcium, phosphorus, whole and intact parathyroid hormone, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide, tartrate-resistant acid phosphatase-5b, Dickkopf-1, fibroblast growth factor, and sclerostin. Rates of detection of osteoporosis by DXA and QCT were compared. Correlations were calculated between baseline biochemical parameters and BMD at baseline and changes over 1 year. Multivariable regression was performed to adjust for age, sex, body mass index, and race.Results Eighty-one patients completed the study (mean age=52.6612.3 years, 56% men, 53% African American, and median dialysis vintage=41 months). At baseline, QCT and DXA of the spine identified similar rates of osteoporosis (13.6% and 13.6%), but at the hip, DXA identified more osteoporosis (22.2% versus 13.6%). At any site and by either method, 33.3% of the patients were osteoporotic. Baseline BMD correlated with sclerostin, intact parathyroid hormone, bone-specific alkaline phosphatase, tartrate-resistant acid phosphatase-5b, and fibroblast growth factor. At 1 year, hip QCT identified a higher number of patients experiencing bone loss (51.3%) than DXA (38.5%). After multivariable adjustment, baseline sclerostin and tartrate-resistant acid phosphatase-5b predicted bone loss measured by QCT of the hip; procollagen type 1 N-terminal propeptide predicted cortical spine bone gain by QCT.Conclusions QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and tartrate-resistant acid phosphatase-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis.

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Section: Discussionsupporting

confidence: 92%

“…Moreover, postmenopausal women treated with a sclerostin antibody were found to have a 5.3% increase in lumbar spine BMD (18). Sclerostin has been shown to be increased in CKD-5D patients (38). A strong inverse relationship was observed between GFR and serum sclerostin (39).…”

Section: Discussionmentioning

confidence: 99%

Bone Mineral Density and Serum Biochemical Predictors of Bone Loss in Patients with CKD on Dialysis

Malluche¹,

Davenport

Cantor³

et al. 2014

Clinical Journal of the American Society of Nephrology

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122

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“…(32)(33)(34) Furthermore, serum levels of the Wnt/b-catenin antagonists, sclerostin (SOST) and Dickkopft-1 (DKK1), were recently reported to be elevated in individuals on dialysis compared to non-CKD individuals, raising the possibility that repression of the b-catenin signaling pathway may also occur in the setting of CKD. (69) The importance of b-catenin signaling on bone mass and remodeling has been well studied. In addition to regulation of osteoclast activity, b-catenin signaling promotes osteogenesis of mesenchymal stem cells, increased osteoblast proliferation, mineralization, and decreased osteoblast apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

240

224

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Chronic kidney disease–mineral bone disorder (CKD‐MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft‐tissue calcification. Emerging evidence suggests that features of CKD‐MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild‐type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD‐MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild‐type mice. To capture the early molecular and cellular events in the progression of CKD‐MBD we examined cell‐specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor‐Ser33/37‐β‐catenin was observed both in mouse and human bones. Overall repression of Wnt/β‐catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF‐κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late‐stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD‐MBD and suggest that repression of the Wnt/β‐catenin pathway is involved in the pathogenesis of renal osteodystrophy. © 2012 American Society for Bone and Mineral Research.

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“…In this issue of CJASN, Cejka et al (18) hypothesize that sclerostin, a protein expressed by osteocytes, may play an important role in ROD, on the basis of the results of a cross-sectional bone biopsy study done in 60 patients who had stage 5D CKD and were on long-term hemodialysis treatment. Sclerostin is the gene product of SOST, discovered in 2001 (19).…”

mentioning

confidence: 99%

“…Interestingly, Cejka et al (18) found an inverse relation between serum sclerostin and intact PTH (iPTH). Moreover, sclerostin was a strong predictor of bone turnover and osteoblast number.…”

mentioning

confidence: 99%