Pharmacological Modulation of Skeletal Homeostasis

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.