Circulating microRNA expression underlying the association of opioid use with low bone mineral density

Opioid drugs, prescribed for pain management or opioid use disorder, have been associated with decreased BMD and increased fracture risk. Changes in circulating microRNA (miRNA) levels have been observed in opioid-treated patients, and miRNAs are crucial regulators of bone metabolism, but the effects of circulating miRNAs on BMD in the context of opioid use remains unexplored. This study aims to identify circulating miRNAs differentially expressed with opioid use that may explain opioid use effects on BMD. We conducted a cross-sectional analysis of 5692 participants from the Framingham Heart Study Offspring and Third Generation cohorts for which 412 miRNA profiles were obtained via qRT-PCR. BMD measurements were obtained using DXA for most participants, among whom opioid use was reported in 62 (1.1%). We modeled miRNA as a function of opioid use and/or BMD, adjusting for age, sex, and BMI, in linear or logistic regression models. Significant miRNAs associated with both opioid use and BMD were then analyzed using a novel strategy for pathway enrichment to identify biological functions impacted by these miRNAs. We found a significant inverse association between opioid use and BMD after adjusting for covariates (β = -.042, 95% CI = -0.075, -0.007, <i>p</i> = .017). We identified 64 miRNAs associated with BMD and 28 miRNAs associated with opioid use (<i>p</i> < .05). Ten miRNAs were significantly (<i>p</i> < .05) associated with both opioid use and BMD, 9 with opposing effects. Pathway enrichment analysis revealed the involvement of thyrotropin-releasing hormones, phosphatidylserine, vascular endothelial growth factors, integrins, and modulation of calcium and potassium ions. Our study has found preliminary evidence for miRNA-mediated mechanisms by which opioid use impacts bone health, which may guide future translational applications to prevent bone loss in opioid users.