Update in serotonin and bone.
BACKGROUND
Serotonin (5-HT) may be an important regulatory agent in bone, and agents that modify 5-HT signaling, such as selective serotonin reuptake inhibitors (SSRIs), are in widespread clinical use.


METHODS
Evidence was obtained by PubMed search and the author's knowledge of the field.


RESULTS
Recent data suggest that gut-derived 5-HT may mediate the skeletal effects of LDL receptor-related protein 5, stimulating intense interest in a novel mechanism for regulating bone mass. However, the specific biochemical nature of serotonergic pathways influencing bone and their direct and/or indirect effects on bone metabolism are still unclear. The weight of epidemiological evidence suggests that SSRIs are associated with reduced bone mass, increased bone loss, and increased risk of fractures. Interpretation of these studies is complicated by the confounding effects of depression, the usual indication for treatment with SSRIs. The mechanisms for putative SSRI-induced deleterious effects on the skeleton are unknown, and are likely multifactorial.


CONCLUSIONS
5-HT may have regulatory effects on bone. Initial preclinical data suggest that its effects may be deleterious and may be regulated by low-density lipoprotein receptor-related protein 5. These studies need confirmation, as well as elucidation, of the biochemical pathways utilized and the feedback loops involved among bone, gut, and perhaps brain. Paradoxically, targeting of 5-HT synthesis and/or signaling in selective tissues may hold promise as an anabolic intervention for bone. Epidemiological data suggest that clinicians should be vigilant about detection of bone disease in patients who are using SSRIs.
Bliziotes
Michael
M
Department of Medicine, Oregon Health & Science University and Portland VA Medical Center, Portland, Oregon 97239, USA. bliziote@ohsu.edu
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002490:Central Nervous System / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000502:physiology; D026502:LDL-Receptor Related Proteins / Q000502:physiology; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008954:Models, Biological; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C555482:LRP5 protein, human
Ann Fam Med. 2005 Sep-Oct;3(5):449-56
16189062
J Biol Chem. 2006 Aug 18;281(33):23698-711
16790443
J Am Geriatr Soc. 2001 Jun;49(6):732-6
11454111
Cell. 2008 Nov 28;135(5):825-37
19041748
J Epidemiol Community Health. 1999 Jun;53(6):343-7
10396480
Ann N Y Acad Sci. 2008 Oct;1139:268-84
18991872
N Engl J Med. 2009 Mar 5;360(10):957-9
19264685
N Engl J Med. 1998 Sep 24;339(13):875-82
9744971
Bone. 2010 Jan;46(1):13-7
19664737
Arch Intern Med. 2003 Apr 28;163(8):949-57
12719205
Cell. 2009 Sep 4;138(5):976-89
19737523
Aging Clin Exp Res. 2008 Dec;20(6):585-92
19179844
Lancet. 1998 May 2;351(9112):1303-7
9643791
J Biol Chem. 2001 Aug 3;276(31):28961-8
11387323
J Bone Miner Res. 2010 Feb;25(2):415-22
19594297
Endocrinology. 2005 Feb;146(2):685-93
15539550
Maturitas. 1999 Oct 24;33(2):133-7
10597877
PLoS One. 2008 Jun 18;3(6):e2423
18560599
Nat Med. 2009 Feb;15(2):145-6
19197289
Toxicol Appl Pharmacol. 2007 May 15;221(1):111-8
17383703
Bone. 2010 Jan;46(1):4-12
19591966
Osteoporos Int. 2005 Jun;16(6):610-5
15448988
CMAJ. 2009 Feb 3;180(3):305-13
19188629
J Pharmacol Exp Ther. 2008 Feb;324(2):791-7
18032571
Mol Cell Endocrinol. 2005 Oct 20;242(1-2):1-9
16085354
Nat Med. 2010 Mar;16(3):308-12
20139991
J Am Geriatr Soc. 2002 Oct;50(10):1629-37
12366615
Arch Intern Med. 2007 Jun 25;167(12):1240-5
17592096
Ann Epidemiol. 1999 Jul;9(5):281-2
10976853
J Rheumatol. 2007 Jan;34(1):140-4
17216681
Bone. 2006 Dec;39(6):1313-21
16884969
Am J Epidemiol. 2003 Jul 1;158(1):77-84
12835289
Int Clin Psychopharmacol. 2008 Mar;23(2):84-7
18301122
J Clin Psychopharmacol. 2008 Aug;28(4):411-7
18626268
N Engl J Med. 1987 Feb 12;316(7):363-9
2880292
Psychosom Med. 2004 Jul-Aug;66(4):533-7
15272099
J Cell Biochem. 2006 May 1;98(1):139-51
16408289
Am J Hum Genet. 2002 Jan;70(1):11-9
11741193
Bone. 2010 Apr;46(4):985-92
20060080
J Geriatr Psychiatry Neurol. 2004 Jun;17(2):88-92
15157349
Am J Med. 2005 Dec;118(12):1414
16378792
Cell Signal. 2006 May;18(5):628-39
16014328
Arch Intern Med. 2007 Jan 22;167(2):188-94
17242321
J Clin Psychopharmacol. 2008 Aug;28(4):384-91
18626264
Cell. 2001 Nov 16;107(4):513-23
11719191
Osteoporos Int. 2005 Aug;16(8):887-97
15618997
J Bone Miner Res. 2003 Jun;18(6):960-74
12817748
Science. 2003 Jan 3;299(5603):76
12511643
Arch Intern Med. 2007 Nov 26;167(21):2329-36
18039992
Osteoporos Int. 2007 Mar;18(3):315-22
17053870
Int Psychogeriatr. 2008 Oct;20(5):890-910
18416875
J Cell Biochem. 2007 May 15;101(2):360-8
17163489
Menopause. 2008 Nov-Dec;15(6):1176-83
18725867
Clin Exp Pharmacol Physiol. 2006 Jul;33(7):575-83
16789923
Gastroenterology. 2007 Jan;132(1):397-414
17241888
J Psychosom Res. 1999 Jan;46(1):29-35
10088979
J Neurosci. 1996 Apr 1;16(7):2352-64
8601815
N Engl J Med. 2002 May 16;346(20):1513-21
12015390
J Am Geriatr Soc. 1999 Jun;47(6):749-54
10366179
Bone. 2001 Nov;29(5):477-86
11704501
J Bone Miner Res. 2004 Sep;19(9):1420-31
15312242
J Gerontol A Biol Sci Med Sci. 2007 Oct;62(10):1172-81
17921433
Endocrinology. 2007 Jun;148(6):2635-43
17395698
Clin Ther. 2006 Apr;28(4):619-30
16750473
J Bone Miner Res. 2009 Apr;24(4):578-88
19049336
J Pharmacol Exp Ther. 2008 Apr;325(1):47-55
18192499
J Bone Miner Res. 2007 Feb;22(2):211-9
17059373
Menopause. 2005 Jan-Feb;12(1):88-91
15668605
Arch Intern Med. 2007 Jun 25;167(12):1246-51
17592097
J Gen Intern Med. 2008 May;23(5):567-74
18286345
J Biol Chem. 1948 Dec;176(3):1243-51
18100415
Osteoporos Int. 2006;17(6):807-16
16520889