Variations of sclerostin with other bone biomarkers over a one-year period in hemodialysis patients

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Published in : Clinica Chimica Acta (2018), vol. 486, pp.183-184, doi : 10.1016/j.cca.2018.08.003 Status : Postprint (Author’s version)

Letter to the editor

Variations of sclerostin with other bone biomarkers over a one-year period

in hemodialysis patients

François Paquota,1_{, Pierre Delanaye}a,1_{, Xavier Warling}b_{, Martial Moonen}b_{, Nicole Smelten}c_{, François Jouret}a_,

Jean-Marie Krzesinskia_{, Nicolas Maillard}d_{, Hans Pottel}e_{, Pieter Evenepoel}f_{, Etienne Cavalier}g a_{Department of Nephrology-Dialysis-Transplantation, University of Liège, CHU Sart Tilman (ULg CHU), Liège, Belgium} b_{Department of Nephrology-Dialysis, Centre Hospitalier Regional (CHR) « La Citadelle », Liège, Belgium}

c_{Department of Nephrology-Dialysis, Centre Hospitalier Bois de l'Abbaye et de Hesbaye (CHBAH), Seraing, Belgium} d_{Department of Nephrology-Dialysis-Transplantation, Hôpital Nord, University Jean Monnet, Saint Etienne, France} e_{Department of Public Health and Primary Care, KU, Leuven Campus Kulak Kortrijk, Kortrijk, Belgium}

f_{Department of Nephrology and Renal Transplantation, University of Leuven, University Hospitals Leuven, Leuven, Belgium} g_{Department of Clinical Chemistry, University of Liège (ULg CHU), Liège, Belgium}

KEYWORDS

Sclerostin

Parathyroid hormone Dialysis

Bone turnover

Mineral and bone disorders (MBD) are common in chronic kidney disease (CKD). Bone turnover abnormalities are particularly frequent in dialysis patients [1]. Because bone biopsy is costly and cumbersome, bone biomarkers (BB) are used but their accuracy remains limited. Recent 2017 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines suggest that clinicians should base CKD-MBD therapies on trends or variations (∆) of biomarkers. Thus, repeated measurements of biomarkers are preferred to one-single cross-sectional result. In a recent work, we showed a clinically acceptable correlation between variations of parathyroid hormone (PTH) and different BB, especially over a one-year period [2]. Sclerostin is considered as the protein "linking" mechanical stress and bone formation. This 22 kDa protein acts as an inhibitor of bone formation by inhibiting the Wnt pathway [3]. A potential role for sclerostin in the assessment of bone turnover has been evoked but remains unclear [4]. In the current analysis, we retrospectively followed variations of sclerostin with other BB over a one-year period.

The cohort considered has been previously described [2]. PTH, sclerostin and other BB concentrations were assessed in hemodialysis patients from 3 independent hospitals in Liège (Belgium) and surroundings (Centre Hospitalier Universitaire du Sart Tilman, Centre Hospitalier Regional La Citadelle, Centre Hospitalier du Bois de l'Abbaye) in 2013 and in the same laboratory. The protocol was approved by our Ethics Committee "Comité d'éthique hospitalo-facultaire universitaire de Liège" (Belgian number study: B707201215885). All participants provided an informed signed consent. Blood samples were drawn at the same moment of the day in all patients, before the first dialysis session of the week, and were immediately centrifuged and kept frozen at -80 °C. Samples were collected at baseline, then after 6 weeks, 6 months, and one year. Third-generation PTH (DiaSorin-Liaison, Stillwater, MN), bone alkaline phosphatase (b-ALP), intact serum procollagen type 1 N propeptide (P1NP), tartrate-resistant acid phosphatase 5B (TRAP-5B), and Beta-CrossLaps (CTX) (IDS-iSYS, Boldon, UK) were measured in the same batch and in the same laboratory (Department of Clinical Chemistry, University of Liège) accredited for the ISO 15189 Guideline. Sclerostin (TecoMedical) was measured in the same laboratory but in later batch than other biomarkers. Inter-assay coefficients of variation were below 10% for all measurements [2].

We measured albumin, phosphorus, serum calcium, and C-reactive protein at baseline and after one-year period (Roche Cobas, Mannheim, Germany). Data are expressed as median [quartile 1; quartile 3]. In the cross-sectional analysis, Pearson's coefficients of correlation were calculated between sclerostin and BB at baseline and after one-year. Coefficients of correlation were calculated focusing on the variations of sclerostin (Δsclerostin, in %) and BB (ΔBB, in %) over a one-year period were thus calculated. Moreover, the slopes of different biomarkers were compared over a one-year period (using the 4 available concentrations). Slopes were built and compared by simple linear regression and Pearson correlation.

One hundred thirty-one patients were recruited. Two patients were excluded from the analysis because of extreme PTH variations (from 36 to 1140 and from 1020 to 67 pg/mL). Median age was 73.3 [18.1] year-old and

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55.8% were men. During the follow-up, 36 patients dropped-out the analysis because of death (n = 18), loss of follow-up (n = 8), renal transplantation (n = 8) or hospitalization (n = 2). The total sample analyzed was thus 93. Clinical and biological characteristics of these patients are summarized in Table 1. In the cross-sectional analysis, a significant negative correlation was found between PTH and sclerostin (r = -0.35, 95% CI: -0.52- to -0.16, p = .0006). We also found a negative correlation between sclerostin and b-ALP (r = -0.23, 95% CI: -0.41-to -0.02, p = .0283) and between sclerostin and CTX (r = -0.23, 95% CI: -0.41- -0.41-to -0.02, p = .0296). No correlation was observed between sclerostin and P1NP, or TRAP-5B. Over a one-year period, significant variation of sclerostin were observed: Δsclerostin: -11% [ -25%; 2%]. When the variations of concentrations are considered (Δsclerostin and ΔBB or ΔPTH), no associations were found. Slopes were calculated for each biomarker on 4 available concentrations over one year. Median [interquartile range] (p for different with 0, one sample Wilcoxon test) slope of sclerostin was -0,014 [ -0,029; 0,051] ng/mL/months (p < .0001). Median slopes were - 0.80 [-3.78; 6.45] pg/mL/month (p = .73), 0.29 [-0.12;1.12] µg/L/ month (p < .0001), -4.26 [-64.5; 57.1] ng/L/month (p = .92), 0.97 [-0.83; 3.10] ng/L/month (p < .001), -0.02 [-0.12; 0.051] U/L/ month (p = .077) for PTH, b-ALP, CTX, P1NP and TRAP-5B, respectively. We found no correlation between sclerostin slope and any other BB slopes.

We showed that variations of sclerostin were not associated with variations of any BB, including PTH. In the cross-sectional analysis, we confirmed the negative association between sclerostin and PTH [5-7], but also between sclerostin and b-ALP or CTX [5, 7]. If these cross-sectional associations could only suggest sclerostin as a turnover bio-marker, the exact role of sclerostin remains unclear. Only very limited data are available with sclerostin and bone biopsy. In a study of 60 hemodialysis patients, Cejka et al. demonstrated that sclerostin levels were inversely correlated with bone formation rate, but the ability of sclerostin to make the distinction between low and high bone turnover was low [4]. Moreover, the same authors found no difference of bone turnover in a model between wild-type and sclerostin knockout mice with CKD [8]. The absence of any association between variations of sclerostin and variations of PTH or other biomarkers also preclude the utility of sclerostin as a marker of bone turnover. This absence of concordance could be explained by a different pathological pathway. Indeed, sclerostin has been proposed as an interesting biomarker for bone mass monitoring and/or vascular calcification detection [9, 10]. There are limitations to our study. It is purely observational. In the absence of bone biopsy data and bone mineral density, only a description of concordances and discrepancies between sclerostin and BB evolution can be done. Lastly, sclerostin measurement has been realized with one specific assay, and recent data showed that conclusions could be different using different assays [6].

We showed no association between variation of sclerostin and variation of PTH or BB over a one-year period in a cohort of hemodialysis patients. Our data indicate that sclerostin does not inform on bone turnover abnormalities. Additional research is required to delineate which bone activity is reflected by circulating sclerostin levels.

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Table 1

Clinical and biological characteristics of the patients at baseline.

Sample 93 Age 74.1 [64.5; 81.2] Gender (% men) 53.8% Dry weight (kg) 71 [60; 83] Height (m) (n = 116) 1.62 ± 0.10 BMI (kg/m2_{) (n = 116)} _{25.6 [22.4; 32.4]} Diabetes (%) 41.9% Hypertension (%) 85.0% Dialysis vintage (month) 31.0 [10.8; 53] Therapy (%)

Calcium-based chelator 63.4% Non-Calcium based chelator 30.1% Native vitamin D 83.4% Active vitamin D 24.7%

Cinacalcet 18.3%

Serum calcium (mmol/L) 2.19 ± 0.18 Serum phosphate (mmol/L) 1.49 [1.20; 1.84] Albumin (g/L) 40 [38; 42] C-reactive protein (mg/L) 4.2 [2.1; 8.1] 25-OH vitamin D (ng/mL) 27.1 [15.3; 41.7] 1,25 vitamin D (pg/mL) 18.2 [12.8; 25.5] PTH (pg/mL) 157 [92; 265] b-ALP (µg/L) 25.6 [16; 35.4] CTX (ng/L) 2211 [1196;4181] P1NP (ng/mL) 70.7 [43.8; 118.0] TRAP-5b (U/L) 4.6 [3.2; 6.1] Sclerostin (ng/mL) 1.31 [0.91; 1.85] FUNDING SOURCES

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

DECLARATION OF INTEREST

None.

ACKNOWLEDGEMENTS

Authors thank the data nurses who were involved in the study, Jean Barahira and Arnaud Borsu for CHU Sart Tilman and Chadya Bouidane for CHR, La Citadelle.

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