Skip to main content

Advertisement

SpringerLink
Log in

Elevated Bone Remodeling Markers of CTX and P1NP in Addition to Sclerostin in Patients with X-linked Hypophosphatemia: A Cross-Sectional Controlled Study

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Aspects of bone remodeling have only been scarcely studied in X-linked hypophosphatemia (XLH). In this cross-sectional controlled study, we assessed biochemical indices of bone remodeling and sclerostin in 27 adult patients (median age 47 [range 24–79] years, 19 women, 8 men) with XLH matched with 81 healthy control subjects (1:3) with respect to age-, sex-, and menopausal status. Markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen, CTX) and formation (N-terminal propeptide of type 1 procollagen, P1NP) were higher in XLH patients compared to controls (median [IQR] 810 [500–1340] vs 485 [265–715] ng/l and 90 [57–136] vs 49 [39–65] ug/l, respectively, both p < 0.001) as well as sclerostin (0.81 [0.60–1.18] vs 0.54 [0.45–0.69] ng/ml, p < 0.001). Similar differences were found when comparing currently treated (with phosphate and alfacalcidol) (n = 11) and untreated (n = 16) XLH patients with their respective controls. We found no significant associations with treatment status and indices of bone remodeling or sclerostin although sclerostin tended to be increased in untreated versus treated (p = 0.06). In contrast to previous histomorphometric studies suggesting a low remodeling activity in XLH, these biochemical indices suggest high osteoblast and osteoclast activity. Further studies are needed to ascertain if the higher sclerostin level in XLH is related to osteocyte dysfunction or represents a secondary phenomenon.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wharton B, Bishop N (2003) Rickets. Lancet 362:1389–1400

    Article  CAS  PubMed  Google Scholar 

  2. Drezner MK (2003) Hypophosphatemic rickets. Endocr Dev 6:126–155

    Article  CAS  PubMed  Google Scholar 

  3. Beck-Nielsen SS, Brusgaard K, Rasmussen LM, Brixen K, Brock-Jacobsen B, Poulsen MR, Vestergaard P, Ralston SH, Albagha OM, Poulsen S, Haubek D, Gjorup H, Hintze H, Andersen MG, Heickendorff L, Hjelmborg J, Gram J (2010) Phenotype presentation of hypophosphatemic rickets in adults. Calcif Tissue Int 87:108–119

    Article  CAS  PubMed  Google Scholar 

  4. Marie PJ, Glorieux FH (1982) Bone histomorphometry in asymptomatic adults with hereditary hypophosphatemic vitamin D-resistant osteomalacia. Metab Bone Dis Relat Res 4:249–253

    Article  CAS  PubMed  Google Scholar 

  5. Marie PJ, Glorieux FH (1981) Histomorphometric study of bone remodeling in hypophosphatemic vitamin D-resistant rickets. Metab Bone Dis Relat Res 3:31–38

    Article  CAS  PubMed  Google Scholar 

  6. Reid IR, Murphy WA, Hardy DC, Teitelbaum SL, Bergfeld MA, Whyte MP (1991) X-linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography, and absorptiometry. Am J Med 90:63–69

    Article  CAS  PubMed  Google Scholar 

  7. Glorieux FH, Marie PJ, Pettifor JM, Delvin EE (1980) Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets. N Engl J Med 303:1023–1031

    Article  CAS  PubMed  Google Scholar 

  8. Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ, Silink M (1991) Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med 325:1843–1848

    Article  CAS  PubMed  Google Scholar 

  9. Makitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E (2003) Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 88:3591–3597

    Article  CAS  PubMed  Google Scholar 

  10. Chavassieux P, Portero-Muzy N, Roux JP, Garnero P, Chapurlat R (2015) Are biochemical markers of bone turnover representative of bone histomorphometry in 370 postmenopausal women? J Clin Endocrinol Metab 100:4662–4668

    Article  CAS  PubMed  Google Scholar 

  11. Compton JT, Lee FY (2014) A review of osteocyte function and the emerging importance of sclerostin. J Bone Joint Surg Am 96:1659–1668

    Article  PubMed  PubMed Central  Google Scholar 

  12. Shanbhogue VV, Hansen S, Jorgensen NR, Beck-Nielsen SS (2018) Impact of conventional medical therapy on bone mineral density and bone turnover in adult patients with X-linked hypophosphatemia: a 6-year prospective cohort study. Calcif Tissue Int 102:321–328

    Article  CAS  PubMed  Google Scholar 

  13. Shanbhogue VV, Hansen S, Folkestad L, Brixen K, Beck-Nielsen SS (2015) Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT in adult patients with hypophosphatemic rickets. J Bone Miner Res 30:176–183

    Article  PubMed  Google Scholar 

  14. Beck-Nielsen SS, Brixen K, Gram J, Brusgaard K (2012) Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. J Hum Genet 57:453–458

    Article  CAS  PubMed  Google Scholar 

  15. Shanbhogue VV, Brixen K, Hansen S (2016) Age- and sex-related changes in bone microarchitecture and estimated strength: a three-year prospective study using HRpQCT. J Bone Miner Res 31:1541–1549

    Article  PubMed  Google Scholar 

  16. Nagata Y, Imanishi Y, Ishii A, Kurajoh M, Motoyama K, Morioka T, Naka H, Mori K, Miki T, Emoto M, Inaba M (2011) Evaluation of bone markers in hypophosphatemic rickets/osteomalacia. Endocrine 40:315–317

    Article  CAS  PubMed  Google Scholar 

  17. Ros I, Alvarez L, Guanabens N, Peris P, Monegal A, Vazquez I, Cerda D, Ballesta AM, Munoz-Gomez J (2005) Hypophosphatemic osteomalacia: a report of five cases and evaluation of bone markers. J Bone Miner Metab 23:266–269

    Article  PubMed  Google Scholar 

  18. Zhang X, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Ito T, Vergeire M, Humphrey J, Glorieux FH, Portale AA, Insogna K, Carpenter TO, Peacock M (2016) Pharmacokinetics and pharmacodynamics of a human monoclonal anti-FGF23 antibody (KRN23) in the first multiple ascending-dose trial treating adults with X-linked hypophosphatemia. J Clin Pharmacol 56:176–185

    Article  CAS  PubMed  Google Scholar 

  19. McKenna MJ, Martin-Grace J, Crowley R, Twomey PJ, Kilbane MT (2018) Congenital hypophosphataemia in adults: determinants of bone turnover markers and amelioration of renal phosphate wasting following total parathyroidectomy. J Bone Miner Metab Sep 20 Epub ahead of print:

  20. Rauch F (2009) Bone biopsy: indications and methods. Endocr Dev 16:49–57

    Article  PubMed  Google Scholar 

  21. Millan JL (2013) The role of phosphatases in the initiation of skeletal mineralization. Calcif Tissue Int 93:299–306

    Article  CAS  PubMed  Google Scholar 

  22. White KE, Hum JM, Econs MJ (2014) Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis. Curr Osteoporos Rep 12:252–262

    Article  PubMed  PubMed Central  Google Scholar 

  23. Addison WN, Masica DL, Gray JJ, McKee MD (2010) Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. J Bone Miner Res 25:695–705

    Article  CAS  PubMed  Google Scholar 

  24. Bresler D, Bruder J, Mohnike K, Fraser WD, Rowe PS (2004) Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets. J Endocrinol 183:R1–R9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Palomo T, Glorieux FH, Rauch F (2014) Circulating sclerostin in children and young adults with heritable bone disorders. J Clin Endocrinol Metab 99:E920–E925

    Article  CAS  PubMed  Google Scholar 

  26. Zelenchuk LV, Hedge AM, Rowe PS (2015) SPR4-peptide alters bone metabolism of normal and HYP mice. Bone 72:23–33

    Article  CAS  PubMed  Google Scholar 

  27. Atkins GJ, Rowe PS, Lim HP, Welldon KJ, Ormsby R, Wijenayaka AR, Zelenchuk L, Evdokiou A, Findlay DM (2011) Sclerostin is a locally acting regulator of late-osteoblast/preosteocyte differentiation and regulates mineralization through a MEPE-ASARM-dependent mechanism. J Bone Miner Res 26:1425–1436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ryan ZC, Craig TA, McGee-Lawrence M, Westendorf JJ, Kumar R (2015) Alterations in vitamin D metabolite, parathyroid hormone and fibroblast growth factor-23 concentrations in sclerostin-deficient mice permit the maintenance of a high bone mass. J Steroid Biochem Mol Biol 148:225–231

    Article  CAS  PubMed  Google Scholar 

  29. Frost HM (2003) Bone’s mechanostat: a 2003 update. Anat Rec A Discov Mol Cell Evol Biol 275:1081–1101

    Article  PubMed  Google Scholar 

  30. Veilleux LN, Cheung MS, Glorieux FH, Rauch F (2013) The muscle-bone relationship in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 98:E990–E995

    Article  PubMed  Google Scholar 

  31. Koivula MK, Risteli L, Risteli J (2012) Measurement of aminoterminal propeptide of type I procollagen (PINP) in serum. Clin Biochem 45:920–927

    Article  CAS  PubMed  Google Scholar 

  32. Melkko J, Hellevik T, Risteli L, Risteli J, Smedsrod B (1994) Clearance of NH2-terminal propeptides of types I and III procollagen is a physiological function of the scavenger receptor in liver endothelial cells. J Exp Med 179:405–412

    Article  CAS  PubMed  Google Scholar 

  33. Hlaing TT, Compston JE (2014) Biochemical markers of bone turnover—uses and limitations. Ann Clin Biochem 51:189–202

    Article  PubMed  Google Scholar 

  34. Hardy DC, Murphy WA, Siegel BA, Reid IR, Whyte MP (1989) X-linked hypophosphatemia in adults: prevalence of skeletal radiographic and scintigraphic features. Radiology 171:403–414

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by a grant from The Research Foundation of the Region of Southern Denmark.

Author Contributions

Study design: SH, SBN, VS, NRJ. Study conduct: SBN, VS, SH. Data collection: SBN, VS, SH. Data interpretation: All authors. Drafting manuscript: SH. Revising manuscript: All authors. Approving final version of manuscript: All authors. SH takes responsibility for integrity of the data analysis. SBN is the overall guarantor of the work presented.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Hospital South West Jutland, Esbjerg, Denmark

    Stinus Hansen

  2. Department of Endocrinology, Odense University Hospital, Odense, Denmark

    Vikram V. Shanbhogue

  3. Department of Clinical Biochemistry, Rigshospitalet, Glostrup, Denmark

    Niklas Rye Jørgensen

  4. OPEN, Odense Patient Data Explorative Network, Odense University Hospital/Institute of Clinical Research, University of Southern Denmark, Odense, Denmark

    Niklas Rye Jørgensen

  5. Department of Pediatrics, Kolding Hospital at Lillebaelt Hospital, Kolding, Denmark

    Signe Sparre Beck-Nielsen

  6. Department of Regional Health Research, University of Southern Denmark, Odense, Denmark

    Signe Sparre Beck-Nielsen

Authors
  1. Stinus Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vikram V. Shanbhogue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Niklas Rye Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Signe Sparre Beck-Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stinus Hansen.

Ethics declarations

Conflict of interest

Signe Sparre Beck-Nielsen received a payment from Pharmacosmos for participation in an expert meeting and payments from Kyowa Kirin for invited speeches. She also provides consultancy to Strakan International. Stinus Hansen, Vikram V Shanbhogue and Niklas Rye Jørgensen declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

Informed consent was obtained from all individual participants included in the study and the Regional Scientific Ethical Committee for Southern Denmark approved the study (reference numbers S-20120155 and S-20090069).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 21 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hansen, S., Shanbhogue, V.V., Jørgensen, N.R. et al. Elevated Bone Remodeling Markers of CTX and P1NP in Addition to Sclerostin in Patients with X-linked Hypophosphatemia: A Cross-Sectional Controlled Study. Calcif Tissue Int 104, 591–598 (2019). https://doi.org/10.1007/s00223-019-00526-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-019-00526-z

Keywords

Search

Navigation