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Antidiabetic Drug Administration Prevents Bone Mineral Density Loss: Evidence From a Two-sample Mendelian Randomization Study

Mingzhu Chen, Shuisen Lin, Wanqiong Chen, Xiaoqiang Chen 


The aim of this study was to investigate the effect of common antidiabetic drugs on BMD by two-sample Mendelian randomization (MR). The single nucleotide polymorphisms that were strongly associated with insulin, metformin, rosiglitazone and gliclazide were extracted as instrumental variables (IVs) for MR analysis. The inverse variance weighted (IVW) method was used as the primary MR method to assess the causal effect of antidiabetic drugs on BMD, and other MR methods, including Weighted median, MR Egger and Weighted mode, were used for complementary analysis. Reliability and stability were assessed by the leave-one-out test. In the present work.


Osteoporosis (OP) is a systemic skeletal condition marked by reduced bone density, compromised bone quality and strength, resulting in heightened bone fragility and a greater likelihood of fractures [1]. The typical clinical signs include widespread pain, height reduction, a curved spine, and limited respiratory capacity. These symptoms can significantly impair self-care abilities and life quality [2], especially in middle-aged and elderly individuals, leading to increased mortality rates and healthcare costs. Consequently, OP and fractures related to it have emerged as a critical global health challenge, with their impact potentially equalling that of cardiovascular and cerebrovascular diseases [3, 4]. In an era where societies are increasingly aging, the early prevention and treatment of OP to minimize the incidence of related fractures is an urgent global health priority.

Materials and methods

Study design

In this research endeavor, we undertook an evaluation of the causal impact of antidiabetic medications on BMD utilizing a two-sample Mendelian randomization (MR) approach. We specifically identified four commonly prescribed antidiabetic drugs as the exposures of interest, while BMD served as the primary outcome measure. To facilitate our MR analysis, we extracted Single Nucleotide Polymorphisms (SNPs) as instrumental variables (IVs).

In accordance with the fundamental principles of MR analysis, the chosen IVs had to meet three crucial assumptions. Firstly, they needed to exhibit a robust and significant association with the exposures under investigation, namely, the antidiabetic drugs in our study. Secondly, the selected IVs had to be free from any confounding factors, such as parathyroid hormone/analogues, calcitonin, and estrogen in the context of our study. Lastly, it was imperative that the IVs exerted their effects on the outcome (BMD) solely through their influence on the exposures, rather than through any direct biological mechanisms.


The causal effect of insulin on heel BMD

We initiated our investigation by examining the potential causal relationship between insulin and heel BMD. In this analysis, we incorporated a total of 7 SNPs as IVs for MR. The IVs set exhibited a commendable average F-statistic, with a mean value of 115.047. Additional details regarding these SNPs can be found in S1 File. The results of our MR analysis are concisely summarized in Table 1 and visually depicted in Fig 1A. Our primary MR analysis, conducted using the IVW method, indicated a null effect of insulin on heel BMD (β = 0.765; se = 0.971; P = 0.430). This outcome suggests that the administration of insulin to individuals with diabetes does not appear to mitigate the loss of BMD.


As human societies continue to develop and face the challenges of an aging population, there has been a notable global increase in the incidence of diabetes [18, 19]. This rise is accompanied by a spectrum of acute and chronic complications that pose significant risks to patient health. Notably, among these chronic complications, OP [9] has emerged as a leading cause of persistent, severe pain and functional impairment. This condition is particularly concerning as it markedly increases the likelihood of fractures. Such fractures can lead to high levels of disability, complicating the treatment and rehabilitation process for individuals with diabetes [20, 21]. This intersection of diabetes and osteoporosis presents a complex health issue, necessitating more comprehensive and multidisciplinary approaches to management and care.


In summary, this study showed that antidiabetic drugs can effectively control blood sugar and at the same time play a role in reducing bone loss, thus reducing the occurrence of DMOP. Metformin and gliclazide are recommended to prevent bone loss in diabetic patients.


We sincerely thank the developers of the GWAS dataset.

Citation: Chen M, Lin S, Chen W, Chen X (2024) Antidiabetic drug administration prevents bone mineral density loss: Evidence from a two-sample Mendelian randomization study. PLoS ONE 19(3): e0300009.

Editor: Carlos Alberto Antunes Viegas, Universidade de Trás-os-Montes e Alto Douro: Universidade de Tras-os-Montes e Alto Douro, PORTUGAL

Received: June 27, 2023; Accepted: February 19, 2024; Published: March 7, 2024

Copyright: © 2024 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: This study was supported by the Quanzhou Guiding Science and Technology Project (2021N130S); the Natural Science Foundation of Fujian Province (2022J011457) and Quanzhou Science and Technology Plan Project (2021N061S). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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