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Randomized Controlled Trial
. 2025 Feb 2;40(2):231-240.
doi: 10.1093/jbmr/zjae200.

Pharmacogenetic and microRNA mechanisms of beta blocker use on bone

Christine W Lary  1   2 , Elizabeth J Atkinson  3 , Jennifer Spillane  1 , Zannatun Nayema  1 , Tyler A Roy  2 , Rebecca Peters  2   4 , Griffin T Scott  1 , Hongyu Chen  1 , Archana Nagarajan  1 , Aaron Brown  2 , Katherine J Motyl  2   4   5 , David G Monroe  6 , Sundeep Khosla  6
Affiliations
Randomized Controlled Trial

Pharmacogenetic and microRNA mechanisms of beta blocker use on bone

Christine W Lary et al. J Bone Miner Res. .

Abstract

Motivated by studies showing an association between beta blocker (BB) use and positive bone outcomes, a pilot randomized control trial was performed at the Mayo Clinic which randomized postmenopausal women to placebo, propranolol (40 or 80 mg twice daily), atenolol (50 mg/d), or nebivolol (5 mg/d) to determine changes in bone turnover markers (BTMs) and in BMD over 20 wk. Pharmacogenetic effects and microRNA-mediated mechanisms involving beta adrenergic receptor and related genes have previously been found. We sought to validate these effects and discover new candidates in an ancillary study to the pilot clinical trial. We genotyped all participants and performed microRNA (miRNA) sequencing at baseline and at 20 wk for 24 participants from the atenolol or placebo groups. We discovered several variants in ADRB1, ADRB2, and HDAC4 which showed significant pharmacogenetic effects with BMD at multiple sites and with BTMs. Our miRNA results showed a significant treatment effect for miR-19a-3p over time with atenolol use in the low-responder group compared to placebo. Overall, the longitudinal miRNA analysis showed a large number of miRNAs which were up-regulated over the trial in the low responders but not the high responders compared to placebo, of which miR-19a-3p was one example. Finally, we compared the response to atenolol treatment for cardiovascular traits (pulse and blood pressure) with the response for the bone resorption marker, C-terminal telopeptide, and found a largely independent effect. Our results have implications for personalized therapy and for understanding mechanisms of BB treatment effect on bone.

Keywords: BMD; beta adrenergic signaling; beta blocker; bone mineral density; miRNA; microRNA; osteoporosis; pharmacogenetics; pharmacogenomics.

Plain language summary

Beta blockers, used to regulate heart rate and blood pressure, may also benefit bone health. We studied postmenopausal women receiving a placebo or one of three BBs over 20 wk, analyzing the association of genetic variants and microRNAs with changes in bone outcomes. We found several gene variants associated with these changes, and in women with low response to atenolol, there were significant differences in change in microRNA levels compared to the placebo group. These findings support a potential personalized medicine strategy for use of BBs based on genetic profiles to improve bone health outcomes in postmenopausal women.

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Conflict of interest statement

None declared.

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