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. 2023 Dec 13;25(1):242.
doi: 10.1186/s13075-023-03213-5.

Osteoporosis and osteoarthritis: a bi-directional Mendelian randomization study

Yudun Qu #  1 , Shibo Chen #  1   2 , Mengling Han  3 , Ziqi Gu  1 , Yujie Zhang  4 , Tianxiang Fan  1   2 , Muhui Zeng  1   2 , Guangfeng Ruan  5 , Peihua Cao  1 , Qian Yang  6   7 , Changhai Ding  8   9   10 , Yan Zhang  11 , Zhaohua Zhu  12   13
Affiliations

Osteoporosis and osteoarthritis: a bi-directional Mendelian randomization study

Yudun Qu et al. Arthritis Res Ther. .

Abstract

Objective: To investigate the causal relationship between low bone mineral density (BMD) and osteoarthritis (OA) using Mendelian randomization (MR) design.

Methods: Two-sample bi-directional MR analyses were performed using summary-level information on OA traits from UK Biobank and arcOGEN. Sensitivity analyses including MR-Egger, simple median, weighted median, MR pleiotropy residual sum, and outlier approaches were utilized in conjunction with inverse variance weighting (IVW). Gene ontology (GO) enrichment analyses and expression quantitative trait locus (eQTL) colocalization analyses were used to investigate the potential mechanism and shared genes between osteoporosis (OP) and OA.

Results: The IVW method revealed that genetically predicted low femoral neck BMD was significantly linked with hip (β = 0.105, 95% CI: 0.023-0.188) and knee OA (β = 0.117, 95% CI: 0.049-0.184), but not with other site-specific OA. Genetically predicted low lumber spine BMD was significantly associated with OA at any sites (β = 0.048, 95% CI: 0.011-0.085), knee OA (β = 0.101, 95% CI: 0.045-0.156), and hip OA (β = 0.150, 95% CI: 0.077-0.224). Only hip OA was significantly linked with genetically predicted reduced total bone BMD (β = 0.092, 95% CI: 0.010-0.174). In the reverse MR analyses, no evidence for a causal effect of OA on BMD was found. GO enrichment analysis and eQTL analysis illustrated that DDN and SMAD-3 were the most prominent co-located genes.

Conclusions: These findings suggested that OP may be causally linked to an increased risk of OA, indicating that measures to raise BMD may be effective in preventing OA. More research is required to determine the underlying processes via which OP causes OA.

Keywords: Expression quantitative trait locus analyses; Gene ontology enrichment analyses; Mendelian randomization; Osteoarthritis; Osteoporosis.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Fig. 1
Fig. 1
Workflow of bi-directional MR analysis. A, the fundamental idea of MR analysis: If we cannot randomize the exposure, we can find a randomized instrumental variable to disentangle. ① Instrumental variables were highly correlated with exposure factors. ② Instrumental variables were independent of the outcome. ③ Instrumental variables were not correlated with confounding factors. B, Workflow of our bi-directional MR analysis. MR: Mendelian randomization; BMD: bone mineral density; OA: osteoarthritis; FN: femoral neck; LS: lumbar spine; TB: total body
Fig. 2
Fig. 2
Gene Ontology enrichment analysis of the casual effect of Bone Mineral Density on Osteoarthritis. A, Gene Ontology enrichment analysis of the casual effect of Bone Mineral Density on knee Osteoarthritis. B, Gene Ontology enrichment analysis of the casual effect of Bone Mineral Density on Hip Osteoarthritis. C, Gene Ontology enrichment analysis of the casual effect of Bone Mineral Density on Osteoarthritis at any sites
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