Advertisement

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

  • Stinus HansenEmail author
  • Vikram V. Shanbhogue
  • Niklas Rye Jørgensen
  • Signe Sparre Beck-Nielsen
Original Research
  • 13 Downloads

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.

Keywords

X-linked hypophosphatemia Bone remodeling markers Sclerostin Phosphate Alfacalcidol 

Notes

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.

Compliance with Ethical Standards

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).

Supplementary material

223_2019_526_MOESM1_ESM.docx (21 kb)
Supplementary material 1 (DOCX 21 KB)

References

  1. 1.
    Wharton B, Bishop N (2003) Rickets. Lancet 362:1389–1400CrossRefGoogle Scholar
  2. 2.
    Drezner MK (2003) Hypophosphatemic rickets. Endocr Dev 6:126–155CrossRefGoogle Scholar
  3. 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 87:108–119CrossRefGoogle Scholar
  4. 4.
    Marie PJ, Glorieux FH (1982) Bone histomorphometry in asymptomatic adults with hereditary hypophosphatemic vitamin D-resistant osteomalacia. Metab Bone Dis Relat Res 4:249–253CrossRefGoogle Scholar
  5. 5.
    Marie PJ, Glorieux FH (1981) Histomorphometric study of bone remodeling in hypophosphatemic vitamin D-resistant rickets. Metab Bone Dis Relat Res 3:31–38CrossRefGoogle Scholar
  6. 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 90:63–69CrossRefGoogle Scholar
  7. 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 303:1023–1031CrossRefGoogle Scholar
  8. 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 325:1843–1848CrossRefGoogle Scholar
  9. 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 88:3591–3597CrossRefGoogle Scholar
  10. 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 100:4662–4668CrossRefGoogle Scholar
  11. 11.
    Compton JT, Lee FY (2014) A review of osteocyte function and the emerging importance of sclerostin. J Bone Joint Surg Am 96:1659–1668CrossRefGoogle Scholar
  12. 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 102:321–328CrossRefGoogle Scholar
  13. 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 30:176–183CrossRefGoogle Scholar
  14. 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 57:453–458CrossRefGoogle Scholar
  15. 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 31:1541–1549CrossRefGoogle Scholar
  16. 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 40:315–317CrossRefGoogle Scholar
  17. 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 23:266–269CrossRefGoogle Scholar
  18. 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 56:176–185CrossRefGoogle Scholar
  19. 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:Google Scholar
  20. 20.
    Rauch F (2009) Bone biopsy: indications and methods. Endocr Dev 16:49–57CrossRefGoogle Scholar
  21. 21.
    Millan JL (2013) The role of phosphatases in the initiation of skeletal mineralization. Calcif Tissue Int 93:299–306CrossRefGoogle Scholar
  22. 22.
    White KE, Hum JM, Econs MJ (2014) Hypophosphatemic rickets: revealing novel control points for phosphate homeostasis. Curr Osteoporos Rep 12:252–262CrossRefGoogle Scholar
  23. 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 25:695–705CrossRefGoogle Scholar
  24. 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–R9CrossRefGoogle Scholar
  25. 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–E925CrossRefGoogle Scholar
  26. 26.
    Zelenchuk LV, Hedge AM, Rowe PS (2015) SPR4-peptide alters bone metabolism of normal and HYP mice. Bone 72:23–33CrossRefGoogle Scholar
  27. 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 26:1425–1436CrossRefGoogle Scholar
  28. 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 148:225–231CrossRefGoogle Scholar
  29. 29.
    Frost HM (2003) Bone’s mechanostat: a 2003 update. Anat Rec A Discov Mol Cell Evol Biol 275:1081–1101CrossRefGoogle Scholar
  30. 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–E995CrossRefGoogle Scholar
  31. 31.
    Koivula MK, Risteli L, Risteli J (2012) Measurement of aminoterminal propeptide of type I procollagen (PINP) in serum. Clin Biochem 45:920–927CrossRefGoogle Scholar
  32. 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 179:405–412CrossRefGoogle Scholar
  33. 33.
    Hlaing TT, Compston JE (2014) Biochemical markers of bone turnover—uses and limitations. Ann Clin Biochem 51:189–202CrossRefGoogle Scholar
  34. 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 171:403–414CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of EndocrinologyHospital South West JutlandEsbjergDenmark
  2. 2.Department of EndocrinologyOdense University HospitalOdenseDenmark
  3. 3.Department of Clinical BiochemistryRigshospitaletGlostrupDenmark
  4. 4.OPEN, Odense Patient Data Explorative Network, Odense University Hospital/Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
  5. 5.Department of PediatricsKolding Hospital at Lillebaelt HospitalKoldingDenmark
  6. 6.Department of Regional Health ResearchUniversity of Southern DenmarkOdenseDenmark

Personalised recommendations