Long-term use of fluoxetine accelerates bone loss through the disruption of sphingolipids metabolism in bone marrow adipose tissue

Huili Zhang,Kefeng Li,Yilan Zhang,Jiawen Sun,Yanna Zhao,Guangwu Lin,Shihong Li

doi:10.1038/s41398-020-0819-5

Abstract

Fluoxetine is a commonly prescribed antidepressant, and the mechanisms of increased bone fragility with its long-term use remain largely unknown. Here, we show that long-term administration of fluoxetine induces the disruption of sphingolipids metabolism in bone marrow adipose tissue (BMAT)through the inhibition of acid sphingomyelinase (ASM). Similarly, a significant reduction of the bone volume was observed in mice with ASM knockout (Smpd1−/−). In detail, inhibition of ASM by fluoxetine reduces the sphingosine-1-phosphate (S1P) level in bone marrow adipocytes, leading to the increase of receptor activator of nuclear factor-kappa-Β ligand (RANKL) secretion, a key regulator for the activation of osteoclastogenesis and bone loss, through the upregulation of cyclooxygenase-2 and its enzymatic product prostaglandin E2 (COX-2/PGE2). In contrast, overexpression of ASM by cisplatin normalizes fluoxetine-induced RANKL overproduction. Furthermore, we conducted a clinical trial with L-serine, a precursor of sphingolipids biosynthesis. The results show that oral supplementation of L-serine (250 mg//kg/d) prevents the acceleration of bone loss caused by long-term fluoxetine (12 months) in postmenopausal women with major depressive disorder (mean total hip bone mineral density reduction: −2.0% vs −1.1%, P = 0.006). Our study provides new insights and potential treatment strategy on the bone loss caused by long-term use of fluoxetine.

Highlights

Major depression is one of the most common psychological disorders in older people and has become the leading cause of disease burden around the world[1]
Rats treated with fluoxetine for 6 weeks showed dramatically lower bone mineral density (BMD) and bone volume/tissue volume (BV/TV) compared with the controls treated with saline (Fig. 1b, c)
S1P and ceramide species were the top metabolites positively correlated with BMD, while, SMs species were negatively correlated with BMD changes in bone marrow adipose tissue (BMAT) of rats (Fig. 2i)

Summary

Introduction

Major depression is one of the most common psychological disorders in older people and has become the leading cause of disease burden around the world[1]. Many more women than men are affected, and the incidence of depression is even higher following menopause[2,3]. A study conducted by Timur and Sahin reported that out of 685 women sampled, 56.9% of postmenopausal women suffered from depression[4]. In another study reported recently, the depression frequency was shown to be as high as 59.3% in postmenopausal women[5]. Common side effects of antidepressants include noradrenergic effects (orthostatic hypotension), histaminergic effects (sedation and weight gain), and anticholinergic effects (dry mouth, impaired vision, and constipation)[8]

Methods

Results

Conclusion