Focusing on spinal stenosis: emerging discoveries concerning Alendronate-induced risks and genetic drug targets

Abstract

Background: Spinal stenosis is a common disease in clinical practice, and drug use is one of its potential predisposing factors. Alendronate, a widely used clinical drug for osteoporosis treatment, has the potential to trigger spinal stenosis. Based on the real world, this study aims to deeply investigate the association between spinal stenosis and alendronate, and to explore novel drug targets against spinal stenosis at the genetic level.

Methods: Alendronate patient data from the FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q4 2024 were included in the study, and four pharmacovigilance analytic methods and Bonferroni corrected P-values were applied to the baseline data, and subgroups of data were analyzed. Complementarily, Weibull distribution were applied to further parse the data. Meanwhile, in order to explore therapeutic targets against spinal stenosis, Mendelian randomization analyses were carried out based on eQTLGen consortium data as well as genome-wide association study (GWAS) data from two large independent cohorts. Subsequently, the medicinal value of the identified drug targets was verified by drug prediction and molecular docking techniques.

Results: Pharmacovigilance analysis showed a strong positive signal between alendronate and spinal stenosis, especially in females and older patients. Fourteen significant drug targets were identified. Their medicinal value was verified by drug prediction and molecular docking, obtaining four protein-drug docking model structures.

Conclusions: This study reveals an alendronate-spinal stenosis association, offering insights for clinical prevention. It also identifies new genetic drug targets, opening new treatment pathways for spinal stenosis.

Trial registration: Not applicable.

Keywords: Alendronate; Drug targets; Mendelian randomization; Pharmacovigilance analysis; Spinal stenosis.

Fig. 1

Flow chart showing the analysis process of the study

Fig. 2

Forest plot showing the reporting odds ratio and corresponding 95% confidence intervals for signal detection of alendronate at the preferred term level. The younger group consisted of those individuals with an age of less than 60 years, while the older group encompassed participants with an age of 60 years or greater. The dashed line in the graphical representation of ROR values is labeled as OR = 1, serving as a reference line for comparison of the odds ratios

Fig. 3

Cumulative distribution curve of alendronate by time-to-onset

Fig. 4

Overview of the identification and analysis of potential drug targets

Fig. 5

Forest plots displaying the findings from the validation phase for 19 significant genes

Fig. 6

GO enrichment results for three terms

Fig. 7

KEGG enrichment results

Fig. 8

PPI network built with GeneMANIA

Fig. 9

Docking results of available proteins small molecules. A PDE4D docking Zardaverine, B MCTP2 docking Zardaverine, C DRD4 docking BP 897, D PDE4D docking Zaprinast