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Color Atlas of Pharmacology Bearbeitet von Detlef Bieger, Geraldine O'Sullivan, Heinz Luellmann, Heinz Lüllmann, Klaus Mohr, Albrecht Ziegler, Lutz Hein, Jürgen Wirth Neuausgabe 2005. Taschenbuch. 416 S. Paperback ISBN 978 3 13 781703 1 Format (B x L): 12,5 x 19 cm Zu Inhaltsverzeichnis schnell und portofrei erhältlich bei Die Online-Fachbuchhandlung beck-shop.de ist spezialisiert auf Fachbücher, insbesondere Recht, Steuern und Wirtschaft. Im Sortiment finden Sie alle Medien (Bücher, Zeitschriften, CDs, eBooks, etc.) aller Verlage. Ergänzt wird das Programm durch Services wie Neuerscheinungsdienst oder Zusammenstellungen von Büchern zu Sonderpreisen. Der Shop führt mehr als 8 Millionen Produkte. 330 p Therapy of Selected Diseases Osteoporosis Osteoporosis is defined as a generalized decrease in bone mass (osteopenia) that equally affects bone matrix and mineral content and is associated with a change in spongiosal architecture. This condition predisposes to collapse of vertebral bodies and bone fractures with trivial trauma (e. g., hip fractures). Bone substance is subject to continual remodeling. The equilibrium between bone formation and bone resorption is regulated in a complex manner: a remodeling cycle is initiated by osteoblasts when these stimulate uninucleated osteoclast precursor cells to fuse into large multinucleated cells. Stimulation occurs by direct cell-to-cell contact between osteoblasts and osteoclast precursor cells and is mediated by the RANK ligand on the surface of osteoblasts and its receptor on the osteoclasts (or their precursors), as well as cytokines secreted by osteoblasts. These processes are inhibited by estrogens and a protein secreted by osteoblasts (osteoprotegerin). The osteoclast creates an acidic milieu, enabling minerals to be solubilized, and then phagocytoses the organic matrix. Hormones regulate these events. In hypocalcemia, the parathyroid increases its secretion of parathormone, resulting in enhanced liberation of Ca2+. Calcitonin transfers active osteoclasts into a resting state. Calcitonin given therapeutically relieves pain associated with neoplastic bone metastases and vertebral body collapse. Estrogens diminish bone resorption by (a) inhibiting activation of osteoclasts by osteoblasts and (b) promoting apoptosis of osteoclasts. Idiopathic osteoporosis cannot be prevented by prophylactic therapy, but its development can be delayed. This requires: a healthy lifestyle with plenty of physical exercise (sports, hiking), daily intake of calcium (1000 mg/day Ca2+) and of vitamin D (1000 IU/day). The same principle holds for postmenopausal osteoporosis. Hormone replacement therapy in postmenopausal women has not been successful because of an increased incidence of breast cancers, thromboembolism, and other adverse effects (p. 250). Long-term hormone replacement therapy should no longer be carried out. If osteoporosis has become clinically manifest, attempts can be made at improving the condition by means of drugs, or at least slowing down further deterioration. Besides administration of calcium and vitamin D, the following options are available. Bisphosphonates (N-containing) structurally mimic endogenous pyrophosphate (see formulae), and like the latter are incorporated into the mineral substance of bone. During phagocytosis of the bone matrix, they are taken up by osteoclasts. There, the Ncontaining bisphosphonates inhibit prenylation of G-proteins and thus damage the cells. Accordingly, osteoclast activity levels are lowered by alendronate and risedronate, while osteoclast apoptosis is promoted. The result is a reduction in bone resorption and a decreased risk of bone fractures. Raloxifene exerts an estrogen-like effect on bone, while acting as an estrogen antagonist in the uterus and breast tissue (p. 254). In terms of fracture prophylaxis, its effectiveness appears inferior to that of bisphosphonates. Thromboembolism and edema are reported as adverse effects. It should also be mentioned that intermittent slight elevation in the plasma concentration of parathormone leads to increased formation of bone substance. The likely explanation is that, under this condition, stimulation of osteoblasts is sufficient to induce synthesis of bone matrix but not strong enough to activate osteoclasts. This strategy is applied therapeutically by administration of a fragment (amino acids 1–34) of recombinant human parathormone (teriparatide, s.c.). Lüllmann u. a., Color Atlas of Pharmacology (ISBN 3-13-781703-X) © 2005 Georg Thieme Verlag Osteoporosis 331 A. Bone: normal state and osteoporosis Normal state Osteoporosis Organic bone matrix Bone mineral: hydroxyapatite B. Regulation of bone remodeling Progenitor cells Parathyroid hormone Biphosphonates Fusion Estrogens Estrogens RANKL Apoptosis O PG RANKL Activation G OP (Pre)Osteoblasts Osteoclasts Calcitonin OH HO P O OH O P O Pyrophosphate OH OH OH RANK = receptor activating NF-Κ-B OH RANKL = RANK-Ligand OPG = Osteoprotegerin Bone resorption Stimulation Inhibition HO P C P O CH2 O OH (CH2 )2 Alendronate NH2 Lüllmann u. a., Color Atlas of Pharmacology (ISBN 3-13-781703-X) © 2005 Georg Thieme Verlag