Dissertation (PhD)--University of Stellenbosch, 2003. / ENGLISH ABSTRACT: The Effect of Statins on Bone and Mineral Metabolism
Both statins and amino-bisphosphonates reduce the prenylation of proteins which
are involved in cytoskeletal organization and activation of polarized and motile cells.
Consequently statins have been postulated to affect bone metabolism. We investigated
the effects of different doses of simvastatin (1,5,10 and 20mg/Kg/day), administered orally
over 12 weeks to intact female Sprague-Dawley rats, and the effect of simvastatin
20mg/Kg/day in sham and ovariectomised rats, on femoral bone mineral density (BMD)
and quantitative bone histomorphometry (QBH), compared to controls. Similarly, the affect
of atorvastatin (2,5mg/Kg/day) and pravastatin (10mg/Kg/day) on BMD was investigated
and compared to controls. BMD was decreased by simvastatin 1mg/Kg/day (p = 0.042),
atorvastatin (p = 0,0002) and pravastatin (p = 0.002). The effect on QBH parameters
differed with different doses of simvastatin (ANOVA; p = 0.00012). QBH parameters of
both bone formation and resorption were equivalently and markedly increased by
simvastatin 20mg/Kg/day in two independent groups of intact rats, and reflected by a
relatively unchanged BMD. At lower doses, simvastatin 1mg/Kg/day decreased bone
formation while increasing bone resorption as reflected by a marked decrease in BMD.
Ovariectomised animals receiving simvastatin 20mg/Kg/day showed no change in BMD
relative to the untreated ovariectomised controls, their increase in bone formation was
smaller than in sham-operated rats receiving simvastatin and there was no change in
bone resorption. The dose response curves of simvastatin for bone formation and
resorption differed from each other.
From these studies it is concluded that:-
a) low-dose simvastatin (1mg/Kg/day), atorvastatin 2.5mg/Kg/day) and pravastatin
10mg/Kg/day) decrease BMD in rodents;b) 1mg/Kg/day simvastatin decreases bone formation and increases bone
resorption and is reflected by a reduced BMD;
c) 20mg/Kg/day simvastatin increases bone formation and resorption and results
in an unchanged BMD;
d) the effects of simvastatin on QBH differ at different dosages;
e) the dose-response curves for QBH parameters of bone resorption and bone
formation differ from each other;
f) the effects of simvastatin seen in intact rats are not observed in ovariectomised
rats;
g) simvastatin is unable to prevent the bone loss caused by ovariectomy. / AFRIKAANSE OPSOMMING: Die Effek van Statiene op Been en Mineraal Metabolisme
Beide statiene en aminobisfosfonate verminder die prenelasie van proteïene wat
betrokke is in die sitoskeletale organisasie en aktivering van gepolariseerde en
beweeglike selle. Gevolglik is dit gepostuleer dat statiene ‘n invloed sal hê op been
metabolisme. Ons het die effekte van verskillende dossisse van simvastatien (1, 5, 10 en
20mg/Kg/dag), mondelings toegedien oor 12 weke aan intakte vroulike Sprague-Dawley
rotte, en die effek van simvastatien 20mg/Kg/dag op skyn- en ge-ovariektomeerde rotte,
op femorale been mineral digtheid (BMD) en kwantitatiewe been histomorfometrie (KBH),
vergeleke met kontroles, ondersoek. Op ‘n soortgelyke manier is die effek van
atorvastatien (2,5mg/Kg/day) en pravastatien (10mgKg/dag) op BMD ondersoek en
vergelyk met kontroles. BMD is verminder deur simvastatien 1mg/Kg/dag (p = 0.042),
atorvastatien (p = 0.0002) en pravastatien (p = 0.002). Die effekte op KBH parameters het
verskil met verskillende dossisse van simvastatien (ANOVA; p = 0.00012). KBH
parameters van beide been vormasie en resorpsie is vergelykend en merkbaar verhoog
deur simvastatien 20mg/Kg/dag in twee onafhanklike groepe van intakte rotte en is
vergesel deur ‘n relatiewe onveranderde BMD. Met laer dossisse het simvastatien
1mg/Kg/dag been vormasie verminder terwyl been resorpsie verhoog is en is weerspieël
deur ‘n merkbaar verminderde BMD. Ge-ovariektomeerde diere wat simvastatien
20mg/Kg/dag ontvang het, het geen verandering in BMD relatief tot die onbehandelde geovariektomeerde
kontroles getoon nie, en die toename in been vormasie was kleiner as in
die skyngeopereerde rotte wat simvastatien ontvang het en daar was geen verandering in
been resorpsie nie. Die dosis-respons kurwes vir simvastatien vir been vormasie en
resorpsie het van mekaar verskil.
Uit hierdie studies word die volgende gevolgtrekkings gea) lae-dosis simvastatien (1mg/Kg/dag), atorvastatien 2.5mg/Kg/dag en
pravastatien 10mg/Kg/dag verminder BMD in knaagdiere;
b) 1mg/Kg/dag simvastatien verminder been vormasie en verhoog been resorpsie
en veroorsaak gevolglik ‘n velaging in die BMD;
c) 20mg/Kg/dag simvastatien verhoog been vormasie en resorpsie met ‘n
gevolglike onveranderde BMD;
d) die effekte van simvastatien op KBH verskil met verskillende dossisse;
e) die dosis-repons kurwes van been resorpsie en been vormasie veskil van
mekaar
f) die effekte van simvastatien wat waargeneem in intakte rotte word nie gesien in
ge-ovariektomeerde rotte nie;
g) simvastatien kannie die verlies van been wat veroorsaak word deur
ovariektomie voorkom nie.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/16061 |
| Date | 04 1900 |
| Creators | Maritz, Frans Jacobus |
| Contributors | Hough, F.S., Hulley, P.A., University of Stellenbosch. Faculty of Health Sciences. Dept. of Internal Medicine. |
| Publisher | Stellenbosch : University of Stellenbosch |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | Unknown |
| Type | Thesis |
| Format | 254 leaves : ill. |
| Rights | University of Stellenbosch |
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