Osteoporosis International

, Volume 29, Issue 7, pp 1643–1651 | Cite as

Mutational analysis uncovers monogenic bone disorders in women with pregnancy-associated osteoporosis: three novel mutations in LRP5, COL1A1, and COL1A2

  • S. Butscheidt
  • A. Delsmann
  • T. Rolvien
  • F. Barvencik
  • M. Al-Bughaili
  • S. Mundlos
  • T. Schinke
  • M. Amling
  • U. Kornak
  • R. Oheim
Original Article



Pregnancy was found to be a skeletal risk factor promoting the initial onset of previously unrecognized monogenic bone disorders, thus explaining a proportion of cases with pregnancy-associated osteoporosis. Therapeutic measures should focus in particular on the normalization of the disturbed calcium homeostasis in order to enable the partial skeletal recovery.


Pregnancy-associated osteoporosis (PAO) is a rare skeletal condition, which is characterized by a reduction in bone mineral density (BMD) in the course of pregnancy and lactation. Typical symptoms include vertebral compression fractures and transient osteoporosis of the hip. Since the etiology is not well understood, this prospective study was conducted in order to elucidate the relevance of pathogenic gene variants for the development of PAO.


Seven consecutive cases with the diagnosis of PAO underwent a skeletal assessment (blood tests, DXA, HR-pQCT) and a comprehensive genetic analysis using a custom-designed gene panel.


All cases showed a reduced BMD (DXA T-score, lumbar spine − 3.2 ± 1.0; left femur − 2.2 ± 0.5; right femur − 1.9 ± 0.5), while the spine was affected more severely (p < 0.05). The trabecular and cortical thickness was overall reduced in HR-pQCT, while the trabecular number showed no alterations in most cases. The genetic analysis revealed three novel mutations in LRP5, COL1A1, and COL1A2.


Our data show that previously unrecognized monogenic bone disorders play an important role in PAO. Pregnancy should be considered a skeletal risk factor, which can promote the initial clinical onset of such skeletal disorders. The underlying increased calcium demand is essential in terms of prophylactic and therapeutic measures, which are especially required in individuals with a genetically determined low bone mass. The implementation of this knowledge in clinical practice can enable the partial recovery of the skeleton. Consistent genetic studies are needed to analyze the frequency of pathogenic variants in women with PAO.


Early-onset osteoporosis Genetics Monogenic bone disorders Pregnancy-associated osteoporosis Treatment 


Funding information

This project has received funding from the European Community’s Seventh Framework Programme under grant agreement no. 602300 (SYBIL) and the German Federal Ministry of Education and Research (BMBF) within the project “Detection and Individualized Management of Early Onset Osteoporosis (DIMEOS).”

Compliance with ethical standards

This prospective approach is legitimated by approval through the local ethics committee (No. PV5364) and all investigations were carried out in accordance with the World Medical Association Declaration of Helsinki.

Conflicts of interest


Supplementary material

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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  1. 1.Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Department of OrthopedicsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.Institute of Medical Genetics and Human GeneticsCharité-Universitätsmedizin BerlinBerlinGermany
  4. 4.Berlin-Brandenburg Center for Regenerative TherapiesCharité-Universitätsmedizin BerlinBerlinGermany
  5. 5.Max Planck Institute for Molecular GeneticsFG Development and DiseaseBerlinGermany
  6. 6.National Bone Board, Martin Zeitz Center for Rare DiseasesUniversity Medical Center Hamburg-EppendorfHamburgGermany

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