Peak bone mass is achieved between ages 20 and 40 years, after which aging is associated with inexorable bone loss in both genders. Men achieve a higher peak bone mass and lose 30%-40% less of their cortical and trabecular bone mass than women. Because of the significant impact of the parathyroid hormone (PTH) on calcium and skeletal metabolism, several investigators have evaluated the PTH-calcium axis in an attempt to elucidate the mechanisms accounting for age-related bone loss and osteoporosis. Whereas several studies document elevated PTH levels, the magnitude of such increments, even in studies using the intact assay, have been quite variable and may be partially explained by differences in nutritional status including the vitamin D status of the elderly subjects in these studies. Moreover, there are no significant differences in baseline PTH levels between genders. Dynamic stimulation of an endocrine axis, however, can bring out differences in the axis in question. An accumulating body of animal and human studies suggest that intermittent PTH administration increases bone mass. The description of diurnal rhythms for PTH and indices of bone turnover raises the possibility that the episodic elevations in PTH levels such as seen across a 24-hour cycle, result in an overall anabolic bone remodeling profile, whereas a loss of the amplitude of this rhythm and/or disturbances in its phase result in a negative bone remodeling profile. The limited studies available evaluating PTH diurnal rhythms between genders and in osteoporotic subjects lack accurate definition of PTH circadian amplitude and phase estimates. The kidney plays a central role in overall calcium balance. Despite higher PTH levels, aging is associated with relative hypercalciuria independent of kidney function. There are no studies formally comparing renal calcium handling between genders and in response to aging. The overall goal of this proposal is to test the following hypotheses: 1) that aging is accompanied by relative hyperparathyroidism, as defined by dynamic testing, which is more accentuated in women than in men; 2) that this hyperparathyroidism is manifested by disturbances in PTH rhythm (amplitude and phase), thus resulting in an overall catabolic bone remodeling profile; and 3) that aging is accompanied by a decreased ability of the kidney to retain calcium independent of PTH. Instead of evaluating baseline measurements, an approach that has failed to provide a unifying explanation of the differences in calcium and skeletal metabolism between genders and with aging, we will evaluate our first and third hypotheses using dynamic testing, including calcium-citrate infusions, and renal calcium clearance studies. The second hypothesis, will be tested through the implementation of a constant routine protocol designed to characterize circadian rhythms. Our studies will provide a model to evaluate the interface among calciotropic hormones, bone, and the kidneys. They will elucidate gender- and age-related differences in calcium and skeletal metabolism and will provide an innovative model to further our understanding of osteoporosis.
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