MANIPULATION OF BONE REMODELING IN AGING

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It has been estimated that more than one billion dollars per year is spent on the treatment of fractures in elderly patients who have osteoporosis from age-related bone loss. This cost will elevate steadily as the elderly population of the United States grows and unless means are found to prevent and treat osteoporosis. This project poses to develop strategies that will increase the mass of the adult dog skeleton by manipulating the bone remodeling and thus develop the treatment needed to prevent and/or treat osteoporosis in man. The hypothesis to be tested is that the bone mass of the adult skeleton can be increased by depressing the osteoclast function without depressing osteoblast function, and without altering the normal coupling found in the remodeling system of the adult skeleton. The proposed studies will determine the appropriate agent that will increase bone mass by activating new remodeling units and depressing osteoclastic bone resorption without affecting coupling and bone formation. Also to be studied is the effectiveness of two types of sequential treatment to increase bone mass, and whether this bone mass increase can be maintained for six months or longer. Both in vivo and post-mortem assays for bone remodeling activities and bone mass will be employed: serum (Ca, P, Mg, alkaline phosphatase, iPTH, iCT, T(3), T(4)) and urinary (Ca, P, hydroxyproline, creatinine) biochemistry, whole body Tc-99m-diphosphonate retention, quantitative radiography; photon absorptiometry, histomorphometry of fluorochrome-labeled rib and iliac crest biopsies and post-mortem analyses of radiographs and histomorphometry of fluorochrome-labeled long bones and vertebrae. Our primary endpoint is the determination of increased bone mass. In addition, we plan to evaluate the bone remodeling rate throughout the studies by bone histomorphometry. These studies will further improve our understanding of bone remodeling in the aging skeleton and establish that intermittent rather than continuous therapy will be more effective in the treatment of osteoporosis.