|Year : 2019 | Volume
| Issue : 5 | Page : 1022-1031
|Correlation between serum sclerostin level and bone density status in children on regular hemodialysis
Manal Abd Elsalam1, Maha Zein El-Abden1, Eman Mahmoud2, Zakia Abo Zahab3, Heba Ahmed1
1 Department of Pediatrics, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
2 Department of Endocrinology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
3 Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
Click here for correspondence address and email
|Date of Submission||20-May-2018|
|Date of Decision||17-Jul-2018|
|Date of Acceptance||18-Jul-2018|
|Date of Web Publication||4-Nov-2019|
| Abstract|| |
Bone disease is frequently observed in chronic kidney disease (CKD) and increases a patient’s risk for fracture. Sclerostin is an osteocyte-derived negative regulator of bone formation. We aimed to assess serum sclerostin level as a bone marker in children with CKD on regular hemodialysis (HD) and detect the association between this and bone density status. This cross-sectional comparative study was conducted on 25 children with CKD on HD and 25 age- and sex-matched healthy children, as controls. Their ages ranged from 4 to 18 years. Serum sclerostin levels were measured and dual-energy X-ray absorptiometry scan was performed in the same line with the traditional bone markers. There was a significant increase in serum sclerostin level in patients (1.754 ± 1.31 ng/mL) compared to controls (0.290 ± 0.074 ng/mL) with P = 0.001. Nine patients (36%) had low bone mineral density (BMD) with z score under -2.0, eight of whom had low BMD in both the neck of femur and lumbar spines. There was a significant increase in serum sclerostin levels in the patient-group with low BMD (2.38 ± 0.85 ng/mL) compared with patients with normal BMD (1.4 ± 0.98 ng/mL) (P = 0.001). A significant positive correlation was found between serum sclerostin level and alkaline phosphtase, parathormone with negative correlation with serum calcium. Sclerostin was 100% specific and sensitive in predicting CKD-mineral and bone disorder. Elevated sclerostin levels were consistent with low BMD and appear to be an independent predictor of reduced BMD in children on regular HD.
|How to cite this article:|
Elsalam MA, El-Abden MZ, Mahmoud E, Zahab ZA, Ahmed H. Correlation between serum sclerostin level and bone density status in children on regular hemodialysis. Saudi J Kidney Dis Transpl 2019;30:1022-31
|How to cite this URL:|
Elsalam MA, El-Abden MZ, Mahmoud E, Zahab ZA, Ahmed H. Correlation between serum sclerostin level and bone density status in children on regular hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2021 May 15];30:1022-31. Available from: https://www.sjkdt.org/text.asp?2019/30/5/1022/270256
| Introduction|| |
Bone disease is frequently observed in chronic kidney disease (CKD) and increases a patient’s risk for fracture, cardiovascular (CV) calcification, and mortality. The Kidney Disease Improving Global Outcomes foundation defined a new syndrome incorporating the bone, mineral, and CV disorders, namely CKD–mineral and bone disorders (CKD-MBDs).
The quest for a modifiable reliable biomarker of CV and bone disease in CKD-MBD remains a nephrologist’s challenge. Numerous bone proteins have been associated with CKD-MBD in patients with CKD, such as osteoprotegerin (OPG), fibroblast growth factor 23, bone-specific alkaline phosphatase (ALP), and sclerostin.
Sclerostin is a new and potentially important player in the well-known bone–vascular axis in CKD and end-stage renal disease (ESRD).
Sclerostin is a 21-kDa glycoprotein that inhibits osteoblast differentiation and bone formation,, and is secreted almost exclusively by osteocytes and to a lesser extent by other cell types including osteoclast precursors, renal and vascular cells. In mouse models, dose-dependent decreases in osteocyte scierostin expression have been shown with mechanical loading, and conversely increased sclerostin expression occurs with mechanical unloading., Sclerostin blocks the Wnt signaling pathway in osteoblasts by binding to low-density lipoprotein receptor-related protein 5/6 (LRP-5/6) receptors.,,,
Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis.
In the context of CKD, sclerostin concentrations clearly increase as glomerular filtration rate decreases; whether this is due to reduced renal clearance, increased skeletal production, or both is still a subject of debate. Therefore, the biological significance and interpretation of circulating sclerostin levels in CKD remain uncertain.
Only a few studies have examined serum sclerostin levels in adult patients with CKD, with particularly few studies in dialysis patients,,, in whom bone metabolism can be abnormally regulated under both high and low turnover conditions. The hypothesis is that CKD-MBD is a complex disease that is not completely understood; however, the aim is to assess serum sclerostin level as one of the factors secreted by the osteocytes that may facilitate the understanding and management and correlate with bone density status.
| Materials and Methods|| |
This is a cross-sectional comparative study, conducted during the period from February 2016 to August 2016. Samples were selected from the nephrology and hemodialysis (HD) units, and from the outpatient pediatric clinic of Alzahraa University Hospital. The study children were divided into two groups: Group I, dialysis group): This included 25 children with ESRD [(estimated glomerular filtration rate) <15 mL/min/l.73 m2] on regular HD for more than three months at the time of the study. They were on regular HD for 4 h, three times weekly, with polysulfone low flux membrane dialyzer, their ages ranged from 5 to 17 years. Furthermore, the study included 25 age- and sex-matched healthy children who served as controls. Children on steroid therapy, children with congenital bone deformity, other chronic illness, and recent fracture were excluded from the study. The study patients were subjected to full history (etiology and duration of CKD and dialysis), and bone symptoms (aches, deformities, and medications).
Informed consent was obtained from the participating parents in adherence to the guidelines of the ethical committee of Alzhraa University Hospital, Al-Azhar University, Cairo, Egypt.
Blood samples were drawn in the morning after an overnight fast of at least 12 h before the start of the mid-week HD session. A 5 mL venous blood sample was withdrawn; 2 mL was mixed with EDTA solution and tested for complete blood picture. 3 mL of the samples was left to clot and serum was separated without delay and analyzed for biochemical parameters on the same day, including serum urea creatinine, calcium, phosphorus, ALP, and parathormone (PTH). All samples were tested on HITACHII auto-analyzer.
Two milliliters of the serum sample was stored at −20°C after careful labeling till the time of sclerostin assay; quantitative determination of serum sclerostin concentrations was performed using the ELISA technique. Kits were delivered by Glory bioscience (www. glorybioscience.com).
This study was conducted with the participation of pediatric (nephrology and HD), endocrinology and clinical pathology departments.
Dual X-ray absorptiometry
For the assessment of bone mineral density (BMD), DEXA test was performed by dual-energy X-ray absorptiometry (DEXA) device in the endocrinology department and Alzharaa University Hospital. All BMD measurements were carried out by an experienced technician by using a GE Lunar prodigy DF +16170 DEXA scanner (Norland) with advanced fan-beam technology, the examination was conducted with the patient lying in supine and lateral decubitus positions. The measurement of BMD was carried out on the lumbar spine, and the anteroposterior (AP) images were generated in all patients. Z-score <-2, which was below the expected range for age, was indicative of the diagnosis.
The recommendations included were:
- Measurement at two sites (hip, spine)
- AP images of L1–L4 were used for spine BMD measurement
- Proximal neck of the left femur was used for the hip
- The scanner calculated BMD in grams per square centimeter
- A reference database was consulted, and values and curves were obtained.
| Statistical Analysis|| |
Data were collected, revised, coded, and entered the Statistical Package for the Social Science version 20 (IBM Corp., Armonk, NY, USA). Spearman correlation coefficients were used to assess the correlation between two studied parameters in the same group. Receiver operating characteristic (ROC) curve was used to assess the best cutoff point with sensitivity and specificity.
Interpretation of probability values were as follows: P >0.05 as nonsignificant, P <0.05 as significant and P <0.01 as highly significant.
| Results|| |
There was significant increase in the serum PTH, ALP, and sclerostin levels in the patients-group compared to controls with no significant difference in the serum calcium (Ca) level. There was also a significant increase in serum sclerostin levels in males compared to females among the patients-group [Table 1].
|Table 1: Comparison between the patients group and control group regarding demographic and laboratory data|
Click here to view
[Table 2] shows that nine patients (36%) had low BMD, eight of whom had low BMD in both neck of femur and lumbar spine and one patient had low BMD in lumbar spine only.
[Table 3] shows comparison between patients with normal BMD and those with low BMD regarding the traditional bone markers; it revealed no significant difference between the two groups regarding the serum level of serum Ca, phosphate, PTH and ALP. [Table 3] also shows the comparison between patients with normal and those with low BMD regarding sclerostin level; it shows a significant increase in serum sclerostin level in the patients-group with low BMD.
|Table 3: Comparison between patients with normal and those with low BMD regarding the traditional bone markers|
Click here to view
[Figure 1] shows significant positive correlation between serum sclerostin and PTH levels. [Figure 2] shows significant negative correlation between serum sclerostin and calcium levels. [Figure 3] shows significant positive correlation between serum sclerostin and ALP levels. [Figure 4] shows BMD of lumbar spine in the control with z score of 1.8 and [Figure 5] shows BMD of the lumbar spine in the patient-group with z score of 2.8. [Figure 6] and [Figure 7] show BMD in the neck of femur in one of the controls and the patient-group, z score was 0.8 and -2.6, respectively.
|Figure 3: Correlation between serum sclerostin and alkaline phosphatase levels.|
Click here to view
|Figure 4: Bone mineral density of the lumbar spines with z score (1.8) (one of the control group).|
Click here to view
|Figure 5: Bone mineral density of the lumbar spine with z score (−2.8) in one of the patients group.|
Click here to view
|Figure 6: Bone mineral density in the femur neck, z score (0.8), in one of the control group.|
Click here to view
|Figure 7: Bone mineral density in the femur neck, z score (−2.6) in one of the patients group.|
Click here to view
[Table 4] and [Table 5] and [Figure 8] show the cutoff point, sensitivity, and specificity of serum sclerostin level and BMD of lumbar spine and the head of femur in children on HD for the prediction of CKD-MBD; it was >0.383, 100%, 100%;0.3, 96%, 68%; 0.4, 84%, 85%, respectively.
|Table 4: Comparison between patients with normal and those with low bone mineral density regarding sclerostin level|
Click here to view
|Table 5: Cutoff point, sensitivity, and specificity of serum sclerostin, bone mineral density of the femur neck and lumbar spine in predicting chronic kidney disease-mineral and bone disorder in hemodialysis children|
Click here to view
|Figure 8: Specificity and sensitivity of sclerostin, neck of femur and lumbar spine z score in the prediction of chronic kidney disease-mineral bone disorders.|
Click here to view
| Discussion|| |
To our knowledge, this is the first study reporting serum sclerostin level in children on HD and consequently, the associations between serum sclerostin levels and BMD in these patients. Compared with healthy controls, significant increase in level of serum sclerostin was detected in the HD group. Claes et al reported that plasma concentration of sclerostin tends to increase across the stages of CKD, and is significantly elevated in maintenance HD patients.
The study results were also in agreement with Thambiah et al and Pelletier et al, who reported significant increase in serum sclerostin level in CKD patients, which reveal accumulation of levels with declining renal filtration; whether this is due to decreased clearance or excess production has not yet been fully assessed. These data originate solely in adults.
In the present study, sclerostin levels are significantly higher in boys than in girls; however, age was not associated significantly. Kirmanı et al reported similar findings in a cross-sectional sample of healthy boys and girls aged 6–21 years, in adults; Modder et al also reported similar findings.
On the other hand, Fischer et al reported that sclerostin levels were independent of age and gender.
The reasons for higher serum sclerostin in males than females are unclear, but it might reflect total-body skeletal mass; the larger skeleton in men simply may produce and release more sclerostin into the circulation. We found that sclerostin levels positively correlated with PTH and ALP levels and negatively correlated with serum Ca and PTH, which is a central regulator of bone homeostasis and inhibits sclerostin expression. Numerous studies have revealed that osteocytes are crucial target cells for the actions of PTH. PTH promotes new bone formation by down-regulating the expression of sclerostin.,
Chronic excess of PTH, as in primary hyper-parathyroidism or secondary to Ca deficiency, increases the rate of bone remodeling, and can result in loss of bone.
Our results are similar to the report of Kim et al, but are inconsistent with the reports of Mirza et al and, Gennari et al, who reported that PTH correlates negatively with serum sclerostin levels. Jean et al did not observe any association between serum sclerostin and PTH levels.
The cause of this discrepancy is unknown but may be attributed to the observation that uremia leads to skeletal resistance to PTH, and decreases in PTH signaling activity might result in increased production of sclerostin in CKD patients.
In the present study, we measured BMD of the anterior-posterior lumbar spine (L1–L4), and the neck of femur, by DEXA. About 36% of the study patients had low BMD; similarly, Andrade et al, Bakr. and Shepetov et al respectively, reported that 25%, 59.1% and 53.1% of children with CKD had low BMD.
It is not surprising to see significant association between low BMD and serum sclerostin levels in pediatric patients on HD with no significant association with the traditional markers; the main action of sclerostin is a decrease in bone formation through inhibiting osteoblast proliferation, differentiation, and promoting osteoblast apoptosis. There are some studies however, linking the increased plasma sclerostin concentrations in CKD with the development of renal osteodystrophy., It has been demonstrated that serum sclerostin levels correlated negatively with the histomorphometric parameters of bone turnover and osteoblastic number in bone biopsies from HD patients.
Some studies, unexpectedly found that serum sclerostin levels were associated positively with BMD; the disparity may due to older patients studied and longer duration on HD.
ROC curve analysis revealed that the cutoff point of sclerostin between patients and controls is >0.383 (ng/mL) with 100% specificity and sensitivity as a new marker of CKD MBD.
In conclusion, serum sclerostin levels are increased in children on HD with significant association with low BMD values. This study provides a base for further research to elucidate whether changes in sclerostin levels play a significant role in the pathogenesis in growing uremic children.
| Limitations of the Study|| |
Some limitations of the study include: no information could be obtained related to this subject since no data have been published on sclerostin in the pediatric population on HD. In addition, the number of participants was relatively small.
Conflict of interest: None declared.
| References|| |
Jean G, Chazot C. Sclerostin in CKD-MBD: One more paradoxical bone protein? Nephrol Dial Transplant 2013;28:2932-5.
Sigrist MK, Levin A, Er L, McIntyre CW. Elevated osteoprotegerin is associated with all-cause mortality in CKD stage 4 and 5 patients in addition to vascular calcification. Nephrol Dial Transplant 2009;24:3157-62.
Jean G, Terrat JC, Vanel T, et al. High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. Nephrol Dial Transplant 2009;24:2792-6.
Kovesdy CP, Ureche V, Lu JL, Kalantar-Zadeh K. Outcome predictability of serum alkaline phosphatase in men with pre-dialysis CKD. Nephrol Dial Transplant 2010;25:3003-11.
Brandenburg VM, D’Haese P, Deck A, et al. From skeletal to cardiovascular disease in 12 steps-the evolution of sclerostin as a major player in CKD-MBD. Pediatr Nephrol 2016;31:195-206.
Silverman SL. Sclerostin. J Osteoporos 2010;2010:941419.
Lin C, Jiang X, Dai Z, et al. Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res 2009;24:1651-61.
Poole KE, van Bezooijen RL, Loveridge N, et al. Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 2005;19:1842-4.
Robling AG, Niziołek PJ, Baldridge LA, et al. Mechanical stimulation of bone in vivo
reduces osteocyte expression of sost/sclerostin. J Biol Chem 2008;283:5866-75.
Moustafa A, Sugiyama T, Prasad J, et al. Mechanical loading-related changes in osteocyte sclerostin expression in mice are more closely associated with the subsequent osteogenie response than the peak strains engendered. Osteoporos Int 2012;23:1225-34.
Moester MJ, Papapoulos SE, Löwik CW, van Bezooijen RL. Sclerostin: Current knowledge and future perspectives. Calcif Tissue Int 2010;87:99-107.
Kusu N, Laurikkala J, Imanishi M, et al. Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J Biol Chem 2003;278:24113-7.
Li X, Zhang Y, Kang H, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 2005;280:19883-7.
Viaene L, Behets GJ, Claes K, et al. Sclerostin: Another bone-related protein related to all-cause mortality in haemodialysis? Nephrol Dial Transplant 2013;28:3024-30.
Cejka D, Herberth J, Branscum AJ, et al. Sclerostin and Dickkopf-1 in renal osteo-dystrophy. Clin J Am Soc Nephrol 2011;6:877-82.
Cejka D, Jäger-Lansky A, Kieweg H, et al. Sclerostin serum levels correlate positively with bone mineral density and microarchitecture in haemodialysis patients. Nephrol Dial Transplant 2012;27:226-30.
Pelletier S, Dubourg L, Carlier MC, Hadj-Aissa A, Fouque D. The relation between renal function and serum sclerostin in adult patients with CKD. Clin J Am Soc Nephrol 2013;8: 819-23.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 2009;(113):S1-130.
KDIGO. 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150.
Lewiecki EM, Gordon CM, Baim S, et al. Special report on the 2007 adult and pediatric position development conferences of the international society for clinical densitometry. Osteoporos Int 2008;19:1369-78.
Claes KJ, Viaene L, Heye S, Meijers B, d’Haese P, Evenepoel P. Sclerostin: Another vascular calcification inhibitor? J Clin Endocrinol Metab 2013;98:3221-8.
Delanaye P, Krzesinski JM, Warling X, et al. Clinical and biological determinants of scierostin plasma concentration in hemodialysis patients. Nephron Clin Pract 2014;128:127-34.
Thambiah S, Roplekar R, Manghat P, et al. Circulating sclerostin and Dickkopf-1 (DKK1) in predialysis chronic kidney disease (CKD): Relationship with bone density and arterial stiffness. Calcif Tissue Int 2012;90:473-80.
Kirmani S, Amin S, McCready LK, et al. Sclerostin levels during growth in children. Osteoporos Int 2012;23:1123-30.
Mödder UI, Hoey KA, Amin S, et al. Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. J Bone Miner Res 2011;26:373-9.
Fischer DC, Mischek A, Wolf S, et al. Paediatric reference values for the C-terminal fragment of fibroblast-growth factor-23, scierostin, bone-specific alkaline phosphatase and isoform 5b of tartrate-resistant acid phosphatase. Ann Clin Biochem 2012;49:546-53.
Bellido T, Ali AA, Gubrij I, et al. Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: A novel mechanism for hormonal control of osteoblastogenesis. Endocrinology 2005;146: 4577-83.
Keller H, Kneissel M. SOST is a target gene for PTH in bone. Bone 2005;37:148-58.
Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 2007;40:1434-46.
Kim SH, Yoon SY, Lim SK, Rhee Y. The effect of renal dysfunction on circulating sclerostin level in patients with type 2 diabetes. Int J Endocrinol 2014;2014:715908.
Mirza FS, Padhi ID, Raisz LG, Lorenzo JA. Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J Clin Endocrinol Metab 2010;95:1991-7.
Gennari L, Merlotti D, Valenti R, et al. Circulating sclerostin levels and bone turnover in type 1 and type 2 diabetes. J Clin Endocrinol Metab 2012;97:1737-44.
Jean G, Chazot C, Bresson E, Zaoui E, Cavalier E. High serum sclerostin levels are associated with a better outcome in haemo-dialysis patients. Nephron 2016;132:181-90.
Andrade MC, Carvalhaes JT, Carvalho AB, Lazarretti-Castro M, Brandão C. Bone mineral density and bone histomorphometry in children on long-term dialysis. Pediatr Nephrol 2007;22:1767-72.
Bakr AM. Bone mineral density and bone turnover markers in children with chronic renal failure. Pediatr Nephrol 2004;19:1390-3.
Shepetov A, Chingayeva G, Abeuova B, et al. The results of noninvasive bone mineral density studies in children and adults with endstage renal failure on hemodialysis. Nephrol Dial Transplant 2016;31:i470-1.
Drüeke TB, Lafage-Proust MH. Sclerostin: Just one more player in renal bone disease? Clin J Am Soc Nephrol 2011;6:700-3.
Moysés RM, Schiavi sc. Sclerostin, osteo-cytes, and chronic kidney disease – Mineral bone disorder. Semin Dial 2015;28:578-86.
Register TC, Hruska KA, Divers J, et al. Sclerostin is positively associated with bone mineral density in men and women and negatively associated with carotid calcified atherosclerotic plaque in men from the African American-Diabetes Heart Study. J Clin Endocrinol Metab 2014;99:315-21.
Manal Abd Elsalam
Department of Pediatrics, Faculty of Medicine, Al-Azhar University, Cairo
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
| Article Access Statistics|
| Viewed||2226 |
| Printed||59 |
| Emailed||0 |
| PDF Downloaded||257 |
| Comments ||[Add] |