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The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial

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Abstract

Summary

Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo.

Introduction

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite a high bone mass. Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS).

Methods

This was a sub-study of a multicenter, randomized, 18-month placebo-controlled, double-blinded trial with metformin vs. placebo in combination with different insulin regimens (the Copenhagen Insulin and Metformin Therapy trial) in patients with T2DM. BMD in the spine and hip and TBS in the spine were assessed by dual-energy X-ray absorptiometry at baseline and after 18 months follow-up.

Results

Four hundred seven patients were included in this sub-study. There were no between-group differences in BMD or TBS. From baseline to 18 months, TBS decreased significantly in both groups (metformin group, − 0.041 [− 0.055, − 0.027]; placebo group − 0.046 [− 0.058, − 0.034]; both p < 0.001). BMD in the spine and total hip did not change significantly from baseline to 18 months. After adjustments for gender, age, vitamin D, smoking, BMI, duration of T2DM, HbA1c, and insulin dose, the TBS between-group differences increased but remained non-significant. HbA1c was negatively associated with TBS (p = 0.009) as was longer duration of diabetes, with the femoral neck BMD (p = 0.003). Body mass index had a positive effect on the hip and femoral neck BMD (p < 0.001, p = 0.045, respectively).

Conclusions

Eighteen months of treatment with metformin had no significant effect on BMD in the spine and hip or TBS in patients with T2DM compared with a placebo. TBS decreased significantly in both groups.

Trial registration

ClinicalTrials.gov (NCT00657943)

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Funding

This study was funded by Nordsjællands Hospital, the Jascha foundation, the Osteoporosis Association for patients, the foundation of A & J C Tvergaard, the foundation of Captain Lieutenant Harald Jensen and his wife, the Inge and Per Refshalls research grant and the Danish Bone Society travel grant.

Author information

Authors and Affiliations

  1. Department of Endocrinology and Nephrology, Nordsjællands University Hospital, Hillerød, Denmark

    A. K. Nordklint, B. Hemmingsen, L. Tarnow, B. Thorsteinsson & P. Eiken

  2. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    A. K. Nordklint, B. Thorsteinsson, H. Vestergaard & P. Eiken

  3. Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark

    T. P. Almdal

  4. Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark

    P. Vestergaard

  5. Steno Diabetes Center North Jutland, Aalborg, Denmark

    P. Vestergaard

  6. Department of Paediatrics and Adolescent Medicine, Nordsjællands Hospital, Hillerød, Denmark

    L. Lundby-Christensen

  7. Steno Diabetes Center Copenhagen, Gentofte, Denmark

    T. W. Boesgaard & S. S. Lund

  8. Department of Medicine, Zealand University Hospital, Køge, Denmark

    L. Breum

  9. Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark

    B. Gade-Rasmussen & S. Madsbad

  10. Department of Medicine, Gentofte, Copenhagen University Hospital, Hellerup, Denmark

    S. B. Sneppen

  11. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    C. Gluud & B. Hemmingsen

  12. Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    T. Jensen & E. R. Mathiesen

  13. Department of Endocrinology, Bispebjerg, Copenhagen University Hospital, Copenhagen, Denmark

    T. Krarup & H. Perrild

  14. Astra – Zeneca, Gothenburg, Sweden

    S. Madsbad & E. R. Mathiesen

  15. Steno Diabetes Center Sjælland, Holbæk, Denmark

    L. Tarnow

  16. Department of Endocrinology, Herlev, Copenhagen University Hospital, Herlev, Denmark

    H. Vestergaard

  17. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark

    H. Vestergaard

  18. Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

    S. S. Lund

Authors
  1. A. K. Nordklint
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  2. T. P. Almdal
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  3. P. Vestergaard
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  4. L. Lundby-Christensen
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  5. T. W. Boesgaard
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  6. L. Breum
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  7. B. Gade-Rasmussen
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  8. S. B. Sneppen
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  9. C. Gluud
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  10. B. Hemmingsen
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  11. T. Jensen
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  12. T. Krarup
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  13. S. Madsbad
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  14. E. R. Mathiesen
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  15. H. Perrild
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  16. L. Tarnow
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  17. B. Thorsteinsson
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  18. H. Vestergaard
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  19. S. S. Lund
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  20. P. Eiken
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Corresponding author

Correspondence to A. K. Nordklint.

Ethics declarations

A signed informed consent form was obtained from all participants. Both the original trial and the current sub-study were approved by the regional ethical committee (region of Copenhagen journal number H-D-2007-112), the Danish Medicines Agency (journal number 2612-3648), reported to the Danish Data Protection Agency (NOH-2015-034) and registered with ClinicalTrials.gov (NCT00657943). The study was conducted in accordance with the Helsinki Declaration and guidelines of Good Clinical Practice.

Conflicts of interest

Azra Karahasanovic Nordklint owns shares in Novo Nordisk A/S. Pia Eiken is an advisory board member for Amgen and Eli Lilly, and on the speakers’ bureau for Amgen and Eli Lilly, and own shares in Novo Nordisk A/S. Louise Lundby Christensen owns shares in Novo Nordisk A/S. Thomas Almdal owns shares in NovoNordisk A/S. Søren S. Lund has previously published his opinion about the clinical effects of metformin treatment. Søren S. Lund owns shares in Novo Nordisk A/S and shares in dynamically traded investment funds, which may own stocks from pharmaceutical companies. Søren S. Lund has reported former employment at Steno Diabetes Center, which is a diabetes hospital and academic institution previously owned by Novo Nordisk. Søren S. Lund is now employed at Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. Søren S. Lund’s contribution was his alone and does not necessarily reflect the official position of Boehringer Ingelheim; Trine W. Boesgaard owns shares in Novo Nordisk A/S. Trine W. Boesgaard has reported former employment at Steno Diabetes Center, which is a diabetes hospital and academic institution previously owned by Novo Nordisk. Trine W. Boesgaard is now employed at Novo Nordisk. Trine W Boesgaard’s contribution was hers alone and does not necessarily reflect the official position of Novo Nordisk. Peter Vestergaard, Leif Breum, Birthe Gade-Rasmussen, Simone B Sneppen, Christian Gluud, Bianca Hemmingsen, Tonny Jensen, Thure Krarup, Sten Madsbad, Elisabeth R Mathiesen, Hans Perrild, Lise Tarnow, Birger Thorsteinsson and Henrik Vestergaard have no conflicts of interest to declare.

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Nordklint, A.K., Almdal, T.P., Vestergaard, P. et al. The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial. Osteoporos Int 29, 2517–2526 (2018). https://doi.org/10.1007/s00198-018-4637-z

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