Reduction of dietary magnesium by only 50% in the rat disrupts bone and mineral metabolism

Introduction: The objective of this study was to determine the effect of a moderate reduction of dietary magnesium [50% of nutrient requirement (50% NR)] on bone and mineral metabolism in the rat, and to explore possible mechanisms for the resultant reduced bone mass. Methods: Female rats were 6 weeks of age at the start of study. Serum magnesium (Mg), calcium (Ca), parathyroid hormone (PTH), 1,25(OH)(2)-vitamin D, alkaline phosphatase, osteocalcin, and pyridinoline were measured during the study at 3- and 6-month time points in control (dietary Mg of 100% NR) and Mg-deficient animals (dietary Mg at 50% NR). Femurs and tibias were also collected for mineral content analyses, micro-computerized tomography, histomorphometry, and immunohistochemical localization of substance P, TNF alpha, and IL-1 beta at 3 and 6 months. Results: Although no significant change in serum Mg was observed, Mg deficiency developed, as assessed by the reduction in bone Mg content at the 3- and 6-month time points (0.69 +/- 0.05 and 0.62 +/- 0.04% ash, respectively, in the Mg depletion group compared to 0.74 +/- 0.04 and 0.67 +/- 0.04% ash, respectively, in the control group; p=0.0009). Hypercalcemia did not develop. Although serum Ca level remained in the normal range, it fell significantly with Mg depletion at 3 and 6 months (10.4 +/- 0.3 and 9.6 +/- 0.3 mg/dl, respectively, compared to 10.5 +/- 0.4 and 10.1 +/- 0.6 mg/dl, respectively, in the control group; p=0.0076). The fall in serum Ca in the Mg-depleted animals was associated with a fall in serum PTH concentration between 3 and 6 months (603 +/- 286 and 505 +/- 302 pg/ml, respectively, although it was still higher than the control). The serum 1,25(OH)(2)-vitamin D level was significantly lower in the Mg depletion group at 6 months (10.6 +/- 7.1 pg/ml) than in the control (23.5 +/- 12.7 pg/ml) (p < 0.01 by the t-test). In Mg-deficient animals, no difference was noted in markers of bone turnover. Trabecular bone mineral content gain was less over time in the distal femur with Mg deficiency at 3 and 6 months (0.028 +/- 0.005 and 0.038 +/- 0.007 g, respectively, compared to 0.027 +/- 0.004 and 0.048 +/- 0.006 g, respectively, in the control group; p < 0.005). Histomorphometry at these time points demonstrated decreased trabecular bone volume (15.76 +/- 1.93 and 14.19 +/- 1.85%, respectively, compared to 19.24 +/- 3.10 and 17.30 +/- 2.59%, respectively, in the control group; p=0.001). Osteoclast number was also significantly increased with Mg depletion (9.07 +/- 1.21 and 13.84 +/- 2.06, respectively, compared to 7.02 +/- 1.89 and 10.47 +/- 1.33, respectively, in the control group; p=0.0003). Relative to the control, immunohistochemical staining intensity of the neurotransmitter substance P and of the cytokines TNF alpha and IL-1 beta was increased in cells of the bone microenvironment in the Mg depletion group, suggesting that inflammatory cytokines may contribute to bone loss. Conclusion: These data demonstrate that Mg intake of 50% NR in the rat causes a reduced bone mineral content and reduced volume of the distal femur. These changes may be related to altered PTH and 1,25(OH)(2)-vitamin D formation or action as well as to an increase release of substance P and the inflammatory cytokines TNF alpha and IL-1 beta.