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Adults with pathogenic MC4R mutations have increased final height and thereby increased bone mass

Journal of Bone and Mineral Metabolism volume 38, pages 117–125 (2020)Cite this article

Abstract

Pathogenic mutations in the melanocortin-4 receptor (MC4R) are associated with obesity, increased linear growth, and higher bone mass in children, and rodent studies have indicated an effect of the MC4R on bone turnover. Furthermore, GLP-1 receptor agonists (GLP-1 RAs) may influence bone metabolism. However, these associations have not been assessed in adults with pathogenic MC4R mutations. Thus, we wished to assess the impact of the MC4R on bone mass and metabolism. Secondly, we wished to investigate the impact of the GLP-1 RA liraglutide on bone mass in adults with pathogenic MC4R mutations. 17 patients with obesity-causing MC4R mutations (BMI: 35.5 ± 7.6) and 35 matched control participants with common obesity (BMI: 34.3 ± 7.1) underwent a DEXA scan for assessment of bone mineral density (BMD), bone mineral apparent density [BMAD = (BMD/√(bone area)], and bone turnover markers (BTMs). Individuals with a BMI above 28 (14 MC4R mutation carriers and 28 matched control participants) underwent 16 weeks treatment with liraglutide 3.0 mg. The MC4R group had higher BMD [mean difference: 0.065 g/m2 (− 0.008 to 0.138), p = 0.03], but BMAD and BTMS were not different compared to the control group. In response to liraglutide, BMAD increased in the control group, compared to no change in the MC4R group [mean group difference: 0.0007 (0.0001–0.001), p = 0.04]. In conclusion, BMD is increased in MC4R causal obesity compared to common obesity, but when corrected for body size (BMAD), bone mass was not increased, and no evidence of an influence of the MC4R on bone metabolism in adults was found. Liraglutide treatment did not change bone metabolism in MC4R causal obesity, but increased bone mass as measured by BMAD in common obesity.

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Acknowledgements

We would like to thank the study participants and the staff at the Department of Pediatrics and the Children’s Obesity Clinic at Holbæk University Hospital. The project was supported by funding from The Danish Diabetes Academy supported by the Novo Nordisk Foundation, The Lundbeck Foundation, the Novo Nordisk Foundation, the Augustinus Foundation, the Region Zealand Health Scientific Research Foundation, Aase and Ejnar Danielsens Foundation, and supported by the Tripartite Immunometabolism Consortium [TrIC]–Novo Nordisk Foundation; Grant number NNF15CC0018486. This study is part of the research activities in TARGET (The Impact of our Genomes on Individual Treatment Response in Obese Children, http://www.target.ku.dk). The funding sponsors were not involved in study design, collection of data or data analysis, approval of the manuscript, or decision to submit for publication.

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Affiliations

  1. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark

    Eva W. Iepsen, Jinyi Zhang, Jens J. Holst, Jens-Christian Holm & Signe S. Torekov

  2. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Translational Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Eva W. Iepsen, Jinyi Zhang, Jens J. Holst & Signe S. Torekov

  3. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Mette Hollensted & Torben Hansen

  4. Department of Endocrinology, Hvidovre University Hospital, Hvidovre, Denmark

    Sten Madsbad

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

    Niklas R. Jørgensen

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

    Niklas R. Jørgensen

  7. The Children’s Obesity Clinic, European Centre of Management (COM/EASO), Department of Pediatrics, Holbæk University Hospital, Holbæk, Denmark

    Jens-Christian Holm

Authors
  1. Eva W. Iepsen
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  2. Jinyi Zhang
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  3. Mette Hollensted
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  4. Sten Madsbad
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  5. Torben Hansen
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  6. Jens J. Holst
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  7. Niklas R. Jørgensen
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  8. Jens-Christian Holm
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  9. Signe S. Torekov
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Contributions

Conceptualization and methodology: SST, JJH, SM, TH, EWI, and JCH. Formal analysis: JZ and EWI. Investigation: EWI. Resources: MH, TH, NRJ, and JCH. Writing—original draft: EWI with help from SST. Writing, review, and editing: JJH, SM, SST, NRJ, TH, JCH, MH, and JZ. Supervision: SST and JJH. Project administration: EWI. The corresponding authors EWI and SST confirm full access to data and final responsibility for the decision to submit for publication.

Corresponding authors

Correspondence to Eva W. Iepsen or Signe S. Torekov.

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Conflict of interest

TH hold stocks in Novo Nordisk A/S. JJH has acted as consultant and has received speaker honoraria for Novo Nordisk. SM served as a consultant or adviser to: Novartis Pharmaceuticals, Novo Nordisk, Merck, Sharp and Dome, Pfizer A/S, Abbott Laboratories, Sanofi Aventis, Astra Zeneca, Johnson & Johnson, Rosche, Mankind, BMS, Antarcia, Boehringer Ingelheim, Eli Lilly. Amgen Received fee for speaking: Novo Nordisk, Merck, Sharp and Dome, Astra Zeneca, Johnson and Johnson, Abbott Laboratories, Pfizer A/S, Roche, Schering-Plough, Sanofi-Aventis, Eli Lilly, Novartis Pharmaceuticals, BMS, Boehringer Ingelheim. The remaining authors have nothing to disclose.

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Iepsen, E.W., Zhang, J., Hollensted, M. et al. Adults with pathogenic MC4R mutations have increased final height and thereby increased bone mass. J Bone Miner Metab 38, 117–125 (2020). https://doi.org/10.1007/s00774-019-01034-8

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  • DOI: https://doi.org/10.1007/s00774-019-01034-8

Keywords

  • Liraglutide
  • MC4R mutations
  • BMC
  • BMD
  • Bone turnover markers
  • GLP-1 RA
  • BMAD