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The adverse skeletal effects of selective serotonin reuptake inhibitors

Published online by Cambridge University Press:  15 April 2020

E.M. Tsapakis
Affiliation:
Maudsley Hospital & Institute of Psychiatry, King's College London, London, UK, SE5 8AF
Z. Gamie
Affiliation:
Maudsley Hospital & Institute of Psychiatry, King's College London, London, UK, SE5 8AF
G.T. Tran
Affiliation:
Maudsley Hospital & Institute of Psychiatry, King's College London, London, UK, SE5 8AF
S. Adshead
Affiliation:
Maudsley Hospital & Institute of Psychiatry, King's College London, London, UK, SE5 8AF
A. Lampard
Affiliation:
Maudsley Hospital & Institute of Psychiatry, King's College London, London, UK, SE5 8AF
A. Mantalaris
Affiliation:
Maudsley Hospital & Institute of Psychiatry, King's College London, London, UK, SE5 8AF
E. Tsiridis*
Affiliation:
Maudsley Hospital & Institute of Psychiatry, King's College London, London, UK, SE5 8AF
*
*Corresponding author. Direct line: +113 3922621; mob: +77 8685 8586; Secretary: Tel.: +113 3929901; fax: +113 3923290. E-mail address: [email protected] (E. Tsiridis).
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Abstract

Selective serotonin reuptake inhibitors (SSRIs) are a widely used group of antidepressants (ADs) with reported potential detrimental effects on bone mineral density (BMD) and increased fracture risk. Here, a comprehensive review of the in vitro, in vivo and clinical studies to date was carried out using the medical search engines MEDLINE (1950 to September 2010) and EMBASE (1980 to September 2010). Serotonin (5-HT) receptors have been identified on osteoclast, osteoblast and osteocyte cell lines. The effect of SSRIs on bone formation and resorption appears to be governed by the activation of a number of 5-HT receptors on osteoblasts and osteoclasts via endocrine, autocrine/paracrine and neuronal pathways. In vitro, in vivo and clinical collective data appears to indicate that SSRIs have a negative effect on bone at the therapeutic dose levels widely used for the treatment of depression in current clinical practice. Caution may therefore have to be employed with the use of SSRIs in patients at an increased risk of falls and osteoporosis. Further studies are needed in order to fully elicit the role of SSRIs in bone formation and their effects in the low oestrogen state.

Type
Review
Copyright
Copyright © Elsevier Masson SAS 2012

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References

Abrahamsen, B., Brixen, K.Mapping the prescriptiome to fractures in men--a national analysis of prescription history and fracture risk. Osteoporos Int. 20 4: 2009 585597.CrossRefGoogle ScholarPubMed
Bab, I., Yirmiya, R., Depression, Selective serotonin reuptake inhibitors, and osteoporosis. Current Osteoporosis Reports. 8 4: 2010 185191.CrossRefGoogle ScholarPubMed
Battaglino, R.et al.Serotonin regulates osteoclast differentiation through its transporter. J Bone Miner Res. 19 9: 2004 14201431.CrossRefGoogle ScholarPubMed
Battaglino, R.et al.Fluoxetine treatment increases trabecular bone formation in mice. J Cell Biochem. 100 6: 2007 13871394.CrossRefGoogle ScholarPubMed
Bliziotes, M.M.et al.Neurotransmitter action in osteoblasts: expression of a functional system for serotonin receptor activation and reuptake. Bone. 29 5: 2001 477486.CrossRefGoogle ScholarPubMed
Bliziotes, M.et al.Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells. Bone. 39 6: 2006 13131321.CrossRefGoogle ScholarPubMed
Bolo, N.R., Hode, Y., Macher, J.P.Long-term sequestration of fluorinated compounds in tissues after fluvoxamine or fluoxetine treatment: a fluorine magnetic resonance spectroscopy study in vivo. MAGMA. 16 6: 2004 268276.CrossRefGoogle ScholarPubMed
Bolton, J.M.et al.Fracture risk from psychotropic medications: a population-based analysis. J Clin Psychopharmacol. 28 4: 2008 384391.CrossRefGoogle ScholarPubMed
Bonnet, N.et al.Various effects of antidepressant drugs on bone microarchitectecture, mechanical properties and bone remodeling. Toxicol Appl Pharmacol. 221 1: 2007 111118.CrossRefGoogle Scholar
Callebert, J.et al.Evidence for a control of plasma serotonin levels by 5-hydroxytryptamine(2B) receptors in mice. J Pharmacol Exp Ther. 317 2: 2006 724731.CrossRefGoogle ScholarPubMed
Collet, C.et al.The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation. FASEB J. 22 2: 2008 418427.CrossRefGoogle ScholarPubMed
Cornea-Hebert, V.et al.Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol. 409 2: 1999 187209.3.0.CO;2-P>CrossRefGoogle ScholarPubMed
Dahlstroem, A, Fuxe K. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand Suppl 1964;Suppl. 232:1–55.Google Scholar
Diem, S.J.et al.Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 167 12: 2007 12401245.CrossRefGoogle Scholar
Dulawa, S.C.et al.Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology. 29 7: 2004 13211330.CrossRefGoogle ScholarPubMed
Elefteriou, F.et al.Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 434 7032: 2005 514520.CrossRefGoogle Scholar
Ensrud, K.E.et al.Central nervous system active medications and risk for fractures in older women. Arch Intern Med. 163 8: 2003 949957.CrossRefGoogle ScholarPubMed
French, D.D.et al.Outpatient medications and hip fractures in the US: a national veterans study. Drugs Aging. 22 10: 2005 877885.CrossRefGoogle ScholarPubMed
Gill, R.K.et al.Function, expression, and characterization of the serotonin transporter in the native human intestine. Am J Physiol Gastrointest Liver Physiol. 294 1: 2008 G254G262.CrossRefGoogle ScholarPubMed
Graham, S.et al.The effect of beta-blockers on bone metabolism as potential drugs under investigation for osteoporosis and fracture healing. Expert Opin Investig Drugs. 17 9: 2008 12811299.CrossRefGoogle Scholar
Gustafsson, B.I.et al.Serotonin and fluoxetine modulate bone cell function in vitro. J Cell Biochem. 98 1: 2006 139151.CrossRefGoogle ScholarPubMed
Gustafsson, B.I.et al.Long-term serotonin administration leads to higher bone mineral density, affects bone architecture, and leads to higher femoral bone stiffness in rats. J Cell Biochem. 97 6: 2006 12831291.CrossRefGoogle ScholarPubMed
Haney, E.M.et al.Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 167 12: 2007 12461251.CrossRefGoogle ScholarPubMed
Hirai, T.et al.Expression of mRNA for 5-HT2 receptors and proteins related to inactivation of 5-HT in mouse osteoblasts. J Pharmacol Sci. 109 2: 2009 319323.CrossRefGoogle ScholarPubMed
Hoyer, D., Hannon, J.P., Martin, G.R.Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav. 71 4: 2002 533554.CrossRefGoogle ScholarPubMed
Hubbard, R.et al.Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol. 158 1: 2003 7784.CrossRefGoogle ScholarPubMed
Kinjo, M.et al.Bone mineral density in subjects using central nervous system-active medications. Am J Med. 118 12: 2005 1414.CrossRefGoogle ScholarPubMed
Launay, J.M.et al.Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells. FASEB J. 20 11: 2006 18431854.Google ScholarPubMed
Lewis, C.E.et al.Predictors of non-spine fracture in elderly men: the MrOS study. J Bone Miner Res. 22 2: 2007 211219.CrossRefGoogle ScholarPubMed
Liu, B.et al.Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people. Lancet. 351 9112: 1998 13031307.CrossRefGoogle ScholarPubMed
Locker, M.et al.Stepwise control of osteogenic differentiation by 5-HT(2B) receptor signaling: nitric oxide production and phospholipase A2 activation. Cell Signal. 18 5: 2006 628639.CrossRefGoogle ScholarPubMed
Lu, N.Z., Bethea, C.L.Ovarian steroid regulation of 5-HT1A receptor binding and G protein activation in female monkeys. Neuropsychopharmacology. 27 1: 2002 1224.CrossRefGoogle Scholar
McNicol, A., Israels, S.J.Platelet dense granules: structure, function and implications for haemostasis. Thromb Res. 95 1: 1999 118.CrossRefGoogle ScholarPubMed
McQueen, J.K., Wilson, H., Fink, G.Estradiol-17 beta increases serotonin transporter (SERT) mRNA levels and the density of SERT-binding sites in female rat brain. Brain Res Mol Brain Res. 45 1: 1997 1323.CrossRefGoogle ScholarPubMed
McQueen, J.K.et al.Serotonin transporter (SERT) mRNA and binding site densities in male rat brain affected by sex steroids. Brain Res Mol Brain Res. 63 2: 1999 241247.CrossRefGoogle ScholarPubMed
Michelson, D.et al.Bone mineral density in women with depression. N Engl J Med. 335 16: 1996 11761181.CrossRefGoogle ScholarPubMed
Nutt, D.J.et al.Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders. Eur Neuropsychopharmacol. 9 suppl. 3: 1999 S81S86.CrossRefGoogle ScholarPubMed
Pacher, P., Ungvari, Z.Selective serotonin-reuptake inhibitor antidepressants increase the risk of falls and hip fractures in elderly people by inhibiting cardiovascular ion channels. Med Hypotheses. 57 4: 2001 469471.CrossRefGoogle ScholarPubMed
Resnick, R.H., Gray, S.J.Distribution of serotonin (5-hydroxytryptamine) in the human gastrointestinal tract. Gastroenterology. 1961; 41: 119121.CrossRefGoogle ScholarPubMed
Richards, J.B.et al.Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med. 167 2: 2007 188194.CrossRefGoogle ScholarPubMed
Rosen, C.J.Serotonin rising--the bone, brain, bowel connection. N Engl J Med. 360 10: 2009 957959.CrossRefGoogle Scholar
Shi, Y.et al.Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo. Proc Natl Acad Sci U S A. 105 51: 2008 2052920533.CrossRefGoogle ScholarPubMed
Spangler, L.et al.Depressive symptoms, bone loss, and fractures in postmenopausal women. J Gen Intern Med. 23 5: 2008 567574.CrossRefGoogle ScholarPubMed
Takeda, S.et al.Leptin regulates bone formation via the sympathetic nervous system. Cell. 111 3: 2002 305317.CrossRefGoogle ScholarPubMed
Vane, J.R.The release and fate of vaso-active hormones in the circulation. Br J Pharmacol. 35 2: 1969 209242.CrossRefGoogle ScholarPubMed
Verdel, B.M., Souverein, P.C., Egberts, T.C., van Staa, T.P., Leufkens, H.G., de Vries, F.Use of antidepressant drugs and risk of osteoporotic and non-osteoporotic fractures. Bone. 47 3: 2010 604609.CrossRefGoogle ScholarPubMed
Vestergaard, P., Rejnmark, L., Mosekilde, L.Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int. 17 6: 2006 807816.CrossRefGoogle ScholarPubMed
Vestergaard, P., Rejnmark, L., Mosekilde, L.Selective serotonin reuptake inhibitors and other antidepressants and risk of fracture. Calcif Tissue Int. 82 2: 2008 92101.CrossRefGoogle ScholarPubMed
Warden, S.J., Haney, E.M.Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: Evidence from in vitro and animal-based studies. J Musculoskelet Neuronal Interact. 8 2: 2008 121132.Google ScholarPubMed
Warden, S.J.et al.Inhibition of the serotonin (5-hydroxytryptamine) transporter reduces bone accrual during growth. Endocrinology. 146 2: 2005 685693.CrossRefGoogle ScholarPubMed
Warden, S.J.et al.Serotonin (5-hydroxytryptamine) transporter inhibition causes bone loss in adult mice independently of estrogen deficiency. Menopause. 15 6: 2008 11761183.CrossRefGoogle ScholarPubMed
Warden, S.J.et al.Psychotropic drugs have contrasting skeletal effects that are independent of their effects on physical activity levels. Bone. 46 4: 2010 985992.CrossRefGoogle ScholarPubMed
Westbroek, I.et al.Expression of serotonin receptors in bone. J Biol Chem. 276 31: 2001 2896128968.CrossRefGoogle ScholarPubMed
Westbroek, I.et al.Long-term fluoxetine administration does not result in major changes in bone architecture and strength in growing rats. J Cell Biochem. 101 2: 2007 360368.CrossRefGoogle Scholar
Williams, L.J.et al.Selective serotonin reuptake inhibitor use and bone mineral density in women with a history of depression. Int Clin Psychopharmacol. 23 2: 2008 8487.CrossRefGoogle ScholarPubMed
Yadav, V.K.et al.Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell. 135 5: 2008 825837.CrossRefGoogle ScholarPubMed
Yadav, V.K.et al.A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell. 138 5: 2009 976989.CrossRefGoogle ScholarPubMed
Zayzafoon, M.Calcium/calmodulin signaling controls osteoblast growth and differentiation. J Cell Biochem. 97 1: 2006 5670.CrossRefGoogle ScholarPubMed
Zhang, X.et al.Tryptophan hydroxylase-2 controls brain serotonin synthesis. Science. 305 5681: 2004 217.CrossRefGoogle ScholarPubMed
Zhou, F.C.et al.Serotonin transporters are located on the axons beyond the synaptic junctions: anatomical and functional evidence. Brain Res. 805 1–2: 1998 241254.CrossRefGoogle ScholarPubMed
Ziere, G.et al.Selective serotonin reuptake inhibiting antidepressants are associated with an increased risk of nonvertebral fractures. J Clin Psychopharmacol. 28 4: 2008 411417.CrossRefGoogle ScholarPubMed
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