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widespread assumption: serotonin is benign substance that makes people happier
widely accepted that both l-tryp and 5HTP ameliorate depression w/o SEs
but serotonin DOES have SEs
research suggests serotonin hinders formation of new bone-->net loss
supplements increasing serotonin, 5HTP, melatonin, or L-tryptophan detrimental to bone???

Literature Review (September 2009)
Serotonin Production And Bone Health
By Jacob Schor, ND, FABNO
from: http://www.naturalmedicinejournal.com/pdf/liit_rev_seratonin.pdf


L-TRYPTOPHAN
essential aa that incr serotonin & melatonin levels
first isolated in 1901 by Sir Frederick Hopkins
same guy isolated glutathione, got 1929 Nobel Prize
L-tryptophan is precursor to: niacin, serotonin and melatonin
used to be widely used as nutritional supplement for sleep and anxiety
l-tryp mb beneficial to tx: chronic pancreatitis, esophageal ulceration, liver cirrhosis
1989 outbreak of eosinophilic-myalgia syndrome (EMS) attributted to this supp
~1,500 people disabled, killed 37
Japanese producer used GMO bacteria to make the product: etiology of outbreak?
also possible that high doses of l-tryptophan affect histamine release-->EMS (2)
sales of L-tryptophan banned in US 1991-2001
5HTP was still on shelves while L-tryp was banned, thus more commonly used
5HTP is more progressed precursor to serotonin and mb more effective than L-tryp
rate limiting step in serotonin production pathway is converion of L-tryp-->5HTP
5HTP crosses BBB easier than L-tryp
some say using L-tryp better (more naturopathic): it allows body to control serotonin levels

SEROTONIN AND BONE
serotonin weakens skeletal bone
regular usage of l-tryp or 5HTP may do the same

first sign of negative affect of serotonin on bone appeared in May 1998 Lancet
8,239 Canadians txd for hip fx vs controls
use of SSRIs incr odds ratio of hip fracture to 2.4 (4)
other antidepressants also incr hip fx so mechanism unclear
depression may cause incr rates of fx

next: paper by Dutch researchers August 2001
osteoblasts and osteocytes have serotonin receptors that bind serotonin (5)

2001 article by Bliziotes et al
VA Hospital in Portland Oregon
cultured osteoblasts responded to serotonin-->incr effect of parathyroid hormone
PTH pulls Ca+ from bone
March 2002 Bliziotes reports that mice w/o serotonin transporter (5HTP)-->osteopenia
March 2005 Bliziotes reports serotonin role in bone accrual during growth
October 2005 Bliziotes raises concern about skeletal development of pts on serotonin pharma
children suffering from depression have thinner bone density
no consensus that SSRIs are to blame

April 2007
new paper blames other factors for bone loss in depression:
HPA dysfx, incr inflam, reduced physical activity, altered nutrition (Ca+, vit D)

June 2007 Archives of Internal Medicine
bone density of women taking antidepressants
n = 2,722 older women
on SSRIs-->almost 2x yearly bone loss relative to SSRI free population
“Use of SSRIs but not TCAs is associated with an increased rate of bone loss at the hip
in this cohort of older women.”(11)

similar study , same issue: Archives of Internal Medicine, on men
n = 5,995 men
the 160 who used SSRIs had 3.9% lower bone density in the hips
& 5.9% lower bone density in lumbar spine
men using other types of antidepressants-->no bone density changes
(trazodone hydrochloride, tricyclics)
decreases approximate bone loss in individuals on longterm steroids (12)
steroids=#2 cause of medication-induced osteoporosis (2005 Journal of Endocrino Investigat)
fractures often asymptomatic and occur in 30-50% of pts on longterm steroids (13)

February 2008 mechanisms are being investigated
Collett reports the ID of a particular serotonin receptor
receptor mediates serotonin’s impact on bone formation and osteoporosis in aging women (14)

March 2008
paper examines bone densities in 607 Australian women
lower BMD among those taking SSRIs
“BMD among SSRI users was 5.6% lower at the femoral neck…, 6.2% lower at the trochanter…and 4.4% lower at the mid-forearm…than nonusers.” (15)

**loss in bone density resulting from SSRI use is independent of estrogen status
decreased est post hysterectomy, post menopause, with hormone blockade therapy for CA
-->increased bone loss
HRT does not cancel out the accelerated bone loss caused by SSRIs (16)

January 2009
Dutch review
SSRI use is associated with both decreased bone density and incr fx rates
some of fx rate increase is almost immediate (within first 14 days of begin drug) (17)
hypothesis: SSRIs cause incr risk of falling-->more fx

another line of research
Wnt signaling pathways and bone formation
supports association of serotonin and bone loss
Wnt signaling pathways regulate bone activity
family of proteins that coordinate development and maintenance of body parts
one of the transmembrane proteins in this pathway: lrp5
low-density lipoprotein receptor-related prot 5 (lrp5), helps reg bone deposition/removal
mutations of lrp5 gene-->severe osteoporosis or high bone mass syndrome

February 2009 review
increased Wnt signaling strengthens bone, weakens articular cartilage (19)
complex role
another paper published in February
suggested that Wnt signaling did not affect the bone directly:
works indirectly by targeting duodenal enterochromaffin cells in the GI tract
-->reg serotonin production (20)

July 2009 journal Bone
mechanisms of Wnt signalling and serotonin fairly well understood
what it all means clinically still up in the air
serotonin binds 1-b receptor on pre-osteoblastic cells-->inhibits cell development into blast
clasts not affected by serotonin level, keep eating bone
Lrp5 affects how much serotonin is produced in the intestine (21)
interferes w/ serotonin production in gut
blocks enzyme that converts L-tryp to serotonin
((old theory: lrp5 inhibits blasts directly via Wnt/beta-catenin signaling))
exposure to serotonin slows bone cell growth
more lrp5 in gut-->less serotonin, stronger bone

Warden et al in July 2009 Bone
big changes (22)
we know SSRIs impact bone health
does L-tryptophan? 5HTP?
lrp5-->decr conversion of l-tryptophan to serotonin
?will higher levels of l-tryp achieved via oral supp bypass lrp5 effect on conversion?
?will elevated lrp5 prevent conversion of supp l-tryp-->prevent serotonin increases?

SEROTONIN FOR ULCERS
several interesting papers suggest novel therapeutic uses for l-tryptophan
2005 paper Journal of Pineal Research
melatonin made in the gut from l-tryptophan is, “…highly protective…against the damage
of both the stomach and the pancreas and accelerates the healing of chronic gastric
ulcerations…”(23)

SO
beware
monitor bone density of pts on serotonin influencers

DEPRESSION AND NEED FOR SUN
July 2009 Environmental Health
“effect of sunlight exposure on the cognitive function" of depressed & non
n = 16,800 people, sunlight exposure considered
"dose-response relationship was found between sunlight exposure and cognitive function, and this relationship differed by depression status.”
**depressed pts: 2x+ more sensitive to reduced sunlight than non-depressed
(odds ratio=2.58)(24)
if someone is depressed, getting out into the sun matters more!!!!

References:
1. Belongia EA, Hedberg CW, Gleich GJ, et al. An investigation of the cause of the eosinophilia-myalgia
syndrome associated with tryptophan use. N Engl J Med. 1990 Aug 9;323(6):357-65.
2. Smith MJ, Garrett RH. A heretofore undisclosed crux of eosinophilia-myalgia syndrome: compromised
histamine degradation. Inflamm Res. 2005 Nov;54(11):435-50.
3. Zmilacher K, Battegay R, Gastpar M. L-5-Hydroxytryptophan Alone and in Combination with a Peripheral
Decarboxylase Inhibitor in the Treatment of Depression. Neuropsychobiology. 1988; 20: 28-35.
4. Liu B, Anderson G, Mittmann N, et al. Use of selective serotonin-reuptake inhibitors of tricyclic
antidepressants and risk of hip fractures in elderly people. Lancet. 1998 May 2;351(9112):1303-7.
5. Westbroek I, van der Plas A, de Rooij KE, et al. Expression of serotonin receptors in bone. J Biol Chem. 2001
Aug 3;276(31):28961-8.
6. Bliziotes MM, Eshleman AJ, Zhang XW, Wiren KM. Neurotransmitter action in osteoblasts: expression of a
functional system for serotonin receptor activation and reuptake. Bone. 2001 Nov;29(5):477-86.
7. Bliziotes M, Gunness M, Eshleman A, et al. The role of dopamine and serotonin in regulating bone mass and
strength: studies on dopamine and serotonin transporter null mice. J Musculoskelet Neuronal Interact. 2002
Mar;2(3):291-5.
8. Warden SJ, Robling AG, Sanders MS, et al. Inhibition of the serotonin (5-hydroxytryptamine) transporter
reduces bone accrual during growth. Endocrinology. 2005 Feb;146(2):685-93.
9. Warden SJ, Bliziotes MM, Wiren KM, et al. Neural regulation of bone and the skeletal effects of serotonin (5-
hydroxytryptamine). Mol Cell Endocrinol. 2005 Oct 20;242(1-2):1-9.
10. Weller EB, Weller RA, Kloos AL, et al. Impact of depression and its treatment on the bones of growing
children. Curr Psychiatry Rep. 2007 Apr;9(2):94-8.
11. Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and rates of hip bone loss in older women: the
study of osteoporotic fractures. Arch Intern Med. 2007 Jun 25;167(12):1240-5.
12. Haney EM, Chan BK, Diem SJ, et al. Association of low bone mineral density with selective serotonin
reuptake inhibitor use by older men. Arch Intern Med. 2007 Jun 25;167(12):1246-51.
13. Civitelli R, Ziambaras K. Epidemiology of glucocorticoid-induced osteoporosis. J Endocrinol Invest. 2008
Jul;31(7 Suppl):2-6.
14. Collet C, Schiltz C, Geoffroy V, et al. The serotonin 5-HT2B receptor controls bone mass via osteoblast
recruitment and proliferation. FASEB J. 2008 Feb;22(2):418-27.
15. Williams LJ, Henry MJ, Berk M, et al. Selective serotonin reuptake inhibitor use and bone mineral density in
women with a history of depression. Int Clin Psychopharmacol. 2008 Mar;23(2):84-7.
16. Warden SJ, Nelson IR, Fuchs RK, et al. Serotonin (5-hydroxytryptamine) transporter inhibition causes bone
loss in adult mice independently of estrogen deficiency. Menopause. 2008 Nov-Dec;15(6):1176-83.
17. Vestergaard P. Fracture risks of antidepressants. Expert Rev Neurother. 2009 Jan;9(1):137-41.
18. Kerse N, Flicker L, Pfaff JJ, Draper B, Lautenschlager NT, Sim M, et al. Falls, depression and antidepressants
in later life: a large primary care appraisal. PLoS One. 2008 Jun 18;3(6):e2423.
19. Lodewyckx L, Lories RJ. WNT Signaling in osteoarthritis and osteoporosis: what is the biological
significance for the clinician? Curr Rheumatol Rep. 2009 Feb;11(1):23-30.
20. Williams BO, Insogna KL. Where Wnts went: the exploding field of Lrp5 and Lrp6 signaling in bone. J Bone
Miner Res. 2009 Feb;24(2):171-8.
21. Warden SJ, Robling AG, Haney EM, et al. The emerging role of serotonin (5-hydroxytryptamine) in the
skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5).
Bone. 2009 Jul 8.
22. Warden SJ, Robling AG, Haney EM, et al. The emerging role of serotonin (5-hydroxytryptamine) in the
skeleton and its mediation of the skeletal effects of low-density lipoprotein receptor-related protein 5 (LRP5).
Bone. 2009 Jul 8.
23. Jaworek J, Brzozowski T, Konturek SJ. Melatonin as an organoprotector in the stomach and the pancreas. J
Pineal Res. 2005 Mar;38(2):73-83.
24. Kent ST, McClure LA, Crosson WL, et al. Effect of sunlight exposure on cognitive function among depressed
and non-depressed participants: a REGARDS cross-sectional study. Environ Health. 2009 Jul 28;8(1):34.

About The Author
Jacob Schor ND, FABNO is a graduate of National College of Naturopathic
Medicine and now practices in Denver. He served as president of the
Colorado Association of Naturopathic Physicians, and is now on the board of
directors of the Oncology Association of Naturopathic Physicians and is
recognized as a Fellow by the American Board of Naturopathic Oncology.
He serves on the editorial board for the International Journal of
Naturopathic Medicine. In 2008, he was awarded the Vis Award by the American Association
of Naturopathic Physicians. His writing appears often in Naturopathy Digest and Naturopathic
Doctor News and Review

Comments

( 2 comments — Leave a comment )
hausfrauatu
Sep. 14th, 2009 12:14 am (UTC)
Oh greaaaaaaat. We really have no idea what we're doing with this stuff, really. No free lunch.

liveonearth
Sep. 14th, 2009 01:39 am (UTC)
Umm hmmm. I was wondering why my bones are so brittle all of a sudden. This is another piece of the puzzle.
( 2 comments — Leave a comment )

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