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Pharmacological Modulation of Skeletal Homeostasis

Andersson, Niklas U. LU (2002)
Abstract (Swedish)
Popular Abstract in Swedish

Benskörhet (osteoporos) är en sjukdom, som leder till att benstommen förlorar en del av sitt kalkinnehåll och sin styrka. Benbrott kan därigenom uppstå spontant eller vid lättare påfrestningar. Gastrektomi (kirurgiskt avlägsnade av magsäcken, GX) och ovariektomi (kirurgisk avlägsnade av äggstockarna, OVX) leder till benskörhet hos människa såväl som hos försöksdjur. Medan OVX-inducerad benskörhet tillskrivs förlust av det kvinnliga könshormonet östrogen så vet vi mindre om varför benskörhet uppkommer efter GX. I denna avhandling beskrivs försök som har gjorts för att kartlägga de mekanismer som orsakar benskörhet efter GX och OVX. Både OVX och GX påverkar främst det trabekulära benet (det porösa... (More)
Popular Abstract in Swedish

Benskörhet (osteoporos) är en sjukdom, som leder till att benstommen förlorar en del av sitt kalkinnehåll och sin styrka. Benbrott kan därigenom uppstå spontant eller vid lättare påfrestningar. Gastrektomi (kirurgiskt avlägsnade av magsäcken, GX) och ovariektomi (kirurgisk avlägsnade av äggstockarna, OVX) leder till benskörhet hos människa såväl som hos försöksdjur. Medan OVX-inducerad benskörhet tillskrivs förlust av det kvinnliga könshormonet östrogen så vet vi mindre om varför benskörhet uppkommer efter GX. I denna avhandling beskrivs försök som har gjorts för att kartlägga de mekanismer som orsakar benskörhet efter GX och OVX. Både OVX och GX påverkar främst det trabekulära benet (det porösa ben som finns inuti kotor och ändarna av de långa rörbenen), GX orsakar dessutom benförluster i skallben och det hårda kompakta ben som benämns kortikalt ben. Behandling med alendronat, parathormon (ett kalcium-reglerande hormon som frisätts från bisköldkörteln) eller östrogen kan förhindra benförtunning efter OVX. Benmineralförluster orsakade av GX kan endast förhindras av alendronat. Resultaten tyder på att mekanismen, eller mekanismerna, bakom benförlusterna efter de båda ingreppen skiljer sig åt. Idag finns det ett stort antal genmodifierade musstammar som uppvisar intressanta förändringar i skelettet. Detta har ökat behovet av metoder för att följa förändringar av kalkinnehållet i skelettet under mössens tillväxt och utveckling. Därför har två olika röntgenbaserade tekniker för att mäta benmineraltäthet jämförts. Det var även av intresse att se vilken metod som är mest lämpad för att påvisa effekter av läkemedel som påverkar benmassan. Av de två metoder som har jämförts, visade det sig att datortomografi (pQCT) är bättre lämpad än skelettscanning (DXA) för att tidigt påvisa effekter av läkemedel på benmassan i möss. Vidare har östrogen en mängd viktiga fysiologiska funktioner hos både män och kvinnor. Östrogenbrist ökar risken för benskörhet, hjärt/kärl-sjukdom och reumatoid artrit medan behandling med östrogen minskar risken att utveckla dessa sjukdomar. Tyvärr är östrogenbehandling även förknippad med en ökad risk för bröstcancer och djup ventrombos. Östrogens effekter tros vara medierade via den ena eller båda av de två nu kända östrogenreceptorerna (ERa och ERb). Genom att studera effekterna av östrogen i möss som saknar den ena eller båda av östrogenreceptorerna har receptorspecificiteten i olika vävnader (t.ex. ben och lever) kartlagts. Denna kartläggning kommer att vara till nytta vid utvecklingen av nya läkemedel som bibehåller östrogenets positiva effekter (exempelvis bibehållen benmassa och sänkta kolesterol nivåer) men som samtidigt saknar de negativa effekterna, såsom ökad risk för bröstcancer och djup ventrombos. (Less)
Abstract
Both ovariectomy (OVX) and gastrectomy (GX) cause osteopenia in several animal species including humans. While the effect of OVX has been ascribed to estrogen deficiency, the underlying mechanism behind GX-induced osteopenia is poorly understood. Nutritional deficiencies, including lack of calcium and vitamin D, have been claimed to cause the osteopenia induced by GX. This thesis attempts to clarify the mechanism(s) behind GX- and OVX-evoked osteopenia. The results show that GX-evoked osteopenia differs from that caused by OVX. While both GX and OVX affected mostly trabecular bone, only GX caused bone loss in calvaria and cortical bone indicating different mechanism(s) behind GX- and OVX-evoked osteopenia. While alendronate (a... (More)
Both ovariectomy (OVX) and gastrectomy (GX) cause osteopenia in several animal species including humans. While the effect of OVX has been ascribed to estrogen deficiency, the underlying mechanism behind GX-induced osteopenia is poorly understood. Nutritional deficiencies, including lack of calcium and vitamin D, have been claimed to cause the osteopenia induced by GX. This thesis attempts to clarify the mechanism(s) behind GX- and OVX-evoked osteopenia. The results show that GX-evoked osteopenia differs from that caused by OVX. While both GX and OVX affected mostly trabecular bone, only GX caused bone loss in calvaria and cortical bone indicating different mechanism(s) behind GX- and OVX-evoked osteopenia. While alendronate (a bisphosphonate), parathyroid hormone (PTH) and estrogen treatment prevented OVX-evoked osteopenia, only alendronate but not PTH or estrogen was effective in preventing GX-evoked osteopenia, emphasising the difference between OVX- and GX-evoked bone loss. The recent development of different genetically modified mice with potentially interesting bone phenotypes has increased the demand for effective non-invasive methods to evaluate bone effects in mice during growth and development, and for drug evaluation. Therefore, the usefulness of dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), in the detection of early treatment effects of PTH in OVX mice were evaluated. pQCT proved to be more sensitive than DXA in the detection of bone loss after OVX and increased bone mass after PTH treatment. Finally, estrogen deficiency increases the risk of a wide variety of illnesses, including cardiovascular diseases, obesity, rheumatoid arthritis and osteoporosis, while estrogen substitution reduces the risk of these ailments. However, long-term estrogen replacement therapy is associated with an increased risk of breast cancer and deep venous thrombosis. Estrogen exerts a variety of important physiological effects, probably via activation of the two estrogen receptors ERa and ERb. By comparing the effects of estrogen in mice lacking one or both of the known estrogen receptors with the effects of estrogen in wild type mice the receptor specificity of effects on different estrogen responsive parameters, including skeletal effects were studied. We found that estrogen increased the cortical bone dimenstions in both wild-type and double estrogen receptor knockout mice. An improved understanding of the receptor specificity of different organs is of importance for the development of agents that can maintain the benefits of estrogen but avoid the risks. This thesis has increased our basic knowledge concerning the effects of alendronate, estrogen and PTH on the skeleton as well as improved our understanding of the effectiveness of these drugs in the prevention of GX- and OVX-induced osteopenia in the rat. This knowledge may be of clinical interest when dealing with post-GX osteopenia in humans. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Professor Linde, Anders, Department of Oral Biochemistry, Göteborg University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Farmakologi, toxicology, farmakognosi, farmaci, toxikologi, pharmacy, pharmacognosy, Pharmacological sciences, peripheral quantitative computed tomography., dual energy X-ray absorptiomenty, estrogen, parathyroid hormone, gastrectomy, alendronate, ovariectomy, Bone
pages
140 pages
publisher
Niklas Andersson, Department of Pharmacology, Institute of Physiolological Sciences, BMC F13, Lund University, SE-221 84 LUND, Sweden
defense location
Rune Grubb-salen, BMC, Sölvegatan 19, Lund University, Lund, Sweden
defense date
2002-10-24 09:15
ISBN
91-628-5324-4
language
English
LU publication?
yes
id
79ccc46b-c173-44ba-bf12-a96bfd5b0cbe (old id 464868)
date added to LUP
2007-08-09 15:40:10
date last changed
2016-09-19 08:45:06
@phdthesis{79ccc46b-c173-44ba-bf12-a96bfd5b0cbe,
  abstract     = {Both ovariectomy (OVX) and gastrectomy (GX) cause osteopenia in several animal species including humans. While the effect of OVX has been ascribed to estrogen deficiency, the underlying mechanism behind GX-induced osteopenia is poorly understood. Nutritional deficiencies, including lack of calcium and vitamin D, have been claimed to cause the osteopenia induced by GX. This thesis attempts to clarify the mechanism(s) behind GX- and OVX-evoked osteopenia. The results show that GX-evoked osteopenia differs from that caused by OVX. While both GX and OVX affected mostly trabecular bone, only GX caused bone loss in calvaria and cortical bone indicating different mechanism(s) behind GX- and OVX-evoked osteopenia. While alendronate (a bisphosphonate), parathyroid hormone (PTH) and estrogen treatment prevented OVX-evoked osteopenia, only alendronate but not PTH or estrogen was effective in preventing GX-evoked osteopenia, emphasising the difference between OVX- and GX-evoked bone loss. The recent development of different genetically modified mice with potentially interesting bone phenotypes has increased the demand for effective non-invasive methods to evaluate bone effects in mice during growth and development, and for drug evaluation. Therefore, the usefulness of dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), in the detection of early treatment effects of PTH in OVX mice were evaluated. pQCT proved to be more sensitive than DXA in the detection of bone loss after OVX and increased bone mass after PTH treatment. Finally, estrogen deficiency increases the risk of a wide variety of illnesses, including cardiovascular diseases, obesity, rheumatoid arthritis and osteoporosis, while estrogen substitution reduces the risk of these ailments. However, long-term estrogen replacement therapy is associated with an increased risk of breast cancer and deep venous thrombosis. Estrogen exerts a variety of important physiological effects, probably via activation of the two estrogen receptors ERa and ERb. By comparing the effects of estrogen in mice lacking one or both of the known estrogen receptors with the effects of estrogen in wild type mice the receptor specificity of effects on different estrogen responsive parameters, including skeletal effects were studied. We found that estrogen increased the cortical bone dimenstions in both wild-type and double estrogen receptor knockout mice. An improved understanding of the receptor specificity of different organs is of importance for the development of agents that can maintain the benefits of estrogen but avoid the risks. This thesis has increased our basic knowledge concerning the effects of alendronate, estrogen and PTH on the skeleton as well as improved our understanding of the effectiveness of these drugs in the prevention of GX- and OVX-induced osteopenia in the rat. This knowledge may be of clinical interest when dealing with post-GX osteopenia in humans.},
  author       = {Andersson, Niklas U.},
  isbn         = {91-628-5324-4},
  keyword      = {Farmakologi,toxicology,farmakognosi,farmaci,toxikologi,pharmacy,pharmacognosy,Pharmacological sciences,peripheral quantitative computed tomography.,dual energy X-ray absorptiomenty,estrogen,parathyroid hormone,gastrectomy,alendronate,ovariectomy,Bone},
  language     = {eng},
  pages        = {140},
  publisher    = {Niklas Andersson, Department of Pharmacology, Institute of Physiolological Sciences, BMC F13, Lund University, SE-221 84 LUND, Sweden},
  school       = {Lund University},
  title        = {Pharmacological Modulation of Skeletal Homeostasis},
  year         = {2002},
}