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.

Indiana University-Purdue University Indianapolis (IUPUI) / Signal Transducer and Activator of Transcription 3 (STAT3) is known to be related to bone metabolism. Mutation of STAT3 causes a rare disorder in which serum levels of IgE are elevated. This causes various skeletal problems similar to osteoporosis. To examine the effect of STAT3 in the osteoclast, we obtained two osteoclast specific STAT3 knockout mouse models: one using the CTSK promoter to drive Cre recombinase and another using a TRAP promoter. Examination of these mice at 8 weeks of age revealed a decreased trabecular bone volume in CTSK specific STAT3 knockout mice along with a slight decrease in osteoclast number in both CTSK and TRAP specific STAT3 knockout females. We also noticed changes in bone mineral density and bone mechanical strength in females. These data suggest that STAT3 plays a part in the function of the osteoclast.