Circulating serum microRNAs including senescent miR-31-5p are associated with incident fragility fractures in older postmenopausal women with type 2 diabetes mellitus

Ursula Heilmeier*, Matthias Hackl, Fabian Schroeder, Soheyla Torabi, Puneet Kapoor, Klemens Vierlinger, Gudny Eiriksdottir, Elias Freyr Gudmundsson, Tamara B. Harris, Vilmundur Gudnason, Thomas M. Link, Johannes Grillari, Ann V. Schwartz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


Fragility fractures are an important hallmark of aging and an increasingly recognized complication of Type 2 diabetes (T2D). T2D individuals have been found to exhibit an increased fracture risk despite elevated bone mineral density (BMD) by dual x-ray absorptiometry (DXA). However, BMD and FRAX-scores tend to underestimate fracture risk in T2D. New, reliable biomarkers are therefore needed. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity. Serum miRNA-classifiers were recently found to discriminate T2D women with and without prevalent fragility fractures with high specificity and sensitivity (AUC > 0.90). However, the association of circulating miRNAs with incident fractures in T2D has not been examined yet. In 168 T2D postmenopausal women in the AGES-Reykjavik cohort, miRNAs were extracted from baseline serum and a panel of 10 circulating miRNAs known to be involved in diabetic bone disease and aging was quantified by qPCR and Ct-values extracted. Unadjusted and adjusted Cox proportional hazard models assessed the associations between serum miRNAs and incident fragility fracture. Additionally, Receiver operating curve (ROC) analyses were performed. Of the included 168 T2D postmenopausal women who were on average 77.2 ± 5.6 years old, 70 experienced at least one incident fragility fracture during the mean follow-up of 5.8 ± 2.7 years. We found that 3 serum miRNAs were significantly associated with incident diabetic fragility fracture: while low expression of miR-19b-1-5p was associated with significantly lower risk of incident fragility fracture (HR 0.84 (95% CI: 0.71–0.99, p = 0.0323)), low expression of miR-203a and miR-31-5p was each significantly associated with a higher risk of incident fragility fracture per unit increase in Ct-value (miR-203a: HR 1.29 (95% CI: 1.12–1.49), p = 0.0004, miR-31-5p HR 1.27 (95% CI: 1.06–1.52), p = 0.009). Hazard ratios of the latter two miRNAs remained significant after adjustments for age, body mass index (BMI), areal bone mineral density (aBMD), clinical FRAX or FRAXaBMD. Women with miR-203a and miR-31-5p serum levels in the lowest expression quartiles exhibited a 2.4–3.4-fold larger fracture risk than women with miR-31-5p and miR-203a serum expressions in the highest expression quartile (0.002 ≤ p ≤ 0.039). Women with both miR-203a and miR-31-5p serum levels below the median had a significantly increased fracture risk (Unadjusted HR 3.26 (95% CI: 1.57–6.78, p = 0.001) compared to those with both expression levels above the median, stable to adjustments. We next built a diabetic fragility signature consisting of the 3 miRNAs that showed the largest associations with incident fracture (miR-203a, miR-31-5p, miR-19b-1-5p). This 3-miRNA signature showed with an AUC of 0.722 comparable diagnostic accuracy in identifying incident fractures to any of the clinical parameters such as aBMD, Clinical FRAX or FRAXaBMD alone. When the 3 miRNAs were combined with aBMD, this combined 4-feature signature performed with an AUC of 0.756 (95%CI 0.680, 0.823) significantly better than aBMD alone (AUC 0.666, 95%CI: (0.585, 0.741)) (p = 0.009). Our data indicate that specific serum microRNAs including senescent miR-31-5p are associated with incident fragility fracture in older diabetic women and can significantly improve fracture risk prediction in diabetics when combined with aBMD measurements of the femoral neck.

Original languageEnglish
Article number116308
Pages (from-to)116308
Publication statusPublished - 1 May 2022

Bibliographical note

Funding Information:
The AGES-Reykjavik study is supported by the National Institute on Aging , US National Institutes of Health contract N01-AG-12100 and HHSN27120120022C and the National Institute on Aging Intramural Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). This study also received funding through NIH grant RC1 AR058405 to TML, as well as through the AWS Seedgrant ( P1405046 ) to MH and the EU-FP7 Frailomic ( 305483 ) and SYBIL ( 602300 ) funds awarded to JG. We express our sincere thanks to Prof. Thor Aspelund and Prof. Iryna Lobach for their advice and the Hjartavernd team for their tremendous help in providing the clinical data.

Publisher Copyright:
© 2021

Other keywords

  • Diabetic bone disease
  • Fracture risk
  • FRAX
  • Incident fragility fracture
  • Secondary osteoporosis
  • Serum microRNA
  • Type 2 diabetes mellitus
  • Diabetes Mellitus, Type 2/blood
  • Humans
  • Absorptiometry, Photon
  • Osteoporotic Fractures/blood
  • MicroRNAs/blood
  • Circulating MicroRNA
  • Aged, 80 and over
  • Postmenopause
  • Female
  • Aged
  • Bone Density/genetics


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