Osteoporosis International

, Volume 25, Issue 10, pp 2383–2388 | Cite as

Serum levels of sclerostin, Dickkopf-1, and secreted frizzled-related protein-4 are not changed in individuals with high bone mass causing mutations in LRP5

  • C. A. SimpsonEmail author
  • D. Foer
  • G. S. Lee
  • J. Bihuniak
  • B. Sun
  • R. Sullivan
  • J. Belsky
  • K. L. Insogna
Original Article



We compared circulating levels of Wnt inhibitors among patients with high bone mass mutations in LRP5, unaffected kindred, and unrelated normal controls. Inhibitors were unchanged in affected and unaffected kindred. We saw no meaningful differences between controls and affected individuals. LRP5 signaling may not influence circulating levels of these inhibitors.


It is thought that gain-of-function mutations in LRP5 result in high bone mass syndromes because these allelic variants confer resistance to the actions of endogenous inhibitors of Wnt signaling. We therefore attempted to determine if circulating levels of Wnt inhibitors are altered in patients with gain-of-function mutations in LRP5.


This is a cross-sectional study in a university research center. Serum was collected from consented volunteers known to have either the G171V or N198S gain-of-function mutations in LRP5, kindred members affected with either mutation, unrelated kindred, and unrelated normal age-matched controls. BMD was provided or measured on site.


There were no significant differences found in the serum levels of sclerostin (SOST), Dickkopf-1 (Dkk-1), or secreted frizzled-related protein-4 (SFRP-4) in affected vs. unaffected individuals from different kindreds or when compared to age-matched unrelated normal individuals. Mean serum SOST values in affected and unaffected kindred members and unrelated normal controls were 52.7 ± 6.1, 36.5 ± 9.6, and 54.8 ± 5.4, respectively. For Dkk-1, the values were 25.9 ± 3.4, 25.7 ± 3.0, and 17.3 ± 2.3 and for SFRP-4, 38.1 ± 2.3, 39.8 ± 3.6, and 28.5 ± 1.7. Serum levels of RANKL and osteoprotegerin (OPG) were not different in the three groups.


Circulating levels of endogenous Wnt inhibitors do not change in patients with gain-of-function mutations in LRP5 including Dkk1, which is suppressed by Wnt signaling. It may be that circulating levels of Wnt inhibitors do not reflect changes in target tissues. It is also possible that other mechanisms besides or in addition to resistance in Wnt inhibitors explains the skeletal effects of these mutations.


HBM mutations High bone mass LRP5 Wnt inhibitors 



This work was supported by the Yale Bone Center and in part by CTSA Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Science (NCATS), components of the National Institutes of Health (NIH), and NIH roadmap for Medical Research.

Conflicts of interest



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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2014

Authors and Affiliations

  • C. A. Simpson
    • 1
    Email author
  • D. Foer
    • 1
  • G. S. Lee
    • 1
  • J. Bihuniak
    • 1
  • B. Sun
    • 1
  • R. Sullivan
    • 1
  • J. Belsky
    • 2
  • K. L. Insogna
    • 1
  1. 1.Department of Medicine, Section of EndocrinologyYale School of MedicineNew HavenUSA
  2. 2.Department of MedicineDanbury HospitalDanburyUSA

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