Magnesium Deficiency: Effect on Bone and Mineral

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The objective of this proposal is to increase our understanding of the role of magnesium (Mg) deficiency in the etiology of osteoporosis. While sex steroid deficiency is a major factor in postmenopausal osteoporosis, nutrition is also important. Dietary Mg intake has been associated with bone mass in aging and postmenopausal osteoporosis. Disorders in which Mg deficiency is common such as alcoholism, malabsorption syndrome and diabetes also have an increased risk of osteoporosis. The average dietary Mg intake in women is 68 percent of the RDA indicating that a large proportion of our population have substantial dietary Mg deficits. Severe Mg deficiency in the rat results in impaired bone growth, osteopenia and skeletal fragility. The level of dietary Mg intake that results in osteoporosis in rat or human is unknown. In our proposal, we will employ dietary Mg deprivation in the rat at 10 percent, 25 percent, and 50 percent of recommended nutrient requirement. This reduction in Mg intake reflects levels of dietary Mg inadequacy in our population. Our first specific aim is to determine the dietary intake that will result in Mg deficiency as assessed by bone Mg content. Another specific aim is directed at assessing the effect of these dietary Mg intakes on bone histology, histomorphometry and bone turnover; ie. at what level of Mg intake does osteoporosis occur and is it reflected by alteration in osteoblast and osteoclast activity. The mechanism for the previously observed osteoporosis in severe Mg deficiency is unclear but may involve systemic hormones or local factors regulating bone cell activity. Severe Mg deficiency in humans and rats result in low serum parathyroid hormone (PTH) and 1,25(OH)2-vitamin D which may contribute to reduced bone formation. We will quantify the effects of low Mg intake on calcium homeostasis by determining serum calcium, PTH and 1,25(OH)2-vitamin D levels. The cause of increased osteoclastic bone resorption in severe Mg deficiency is unclear. Cytokines can increase osteoclastic bone resorption and are implicated in postmenopausal osteoporosis. Mg deficiency in the rat results in an increase in serum substance P which in turn stimulates production of various cytokines. We will therefore measure serum substance P, TNFalpha, IL1beta, and IL6 in the Mg deficient rat and perform immunohistochemical staining of bone for these cytokines. Parallel studies will be performed in which a specific substance P receptor inhibitor will be administered to directly test whether generation of these cytokines are responsible for Mg deficiency-induced bone loss. These studies should substantiate our hypothesis that Mg depletion contributes to osteoporosis and provide mechanistic explanations.