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We hypothesized that a zinc-deficient diet alters the mineral (calcium, magnesium, and phosphorus) components of bones, as well as hormones related to bone remodeling, and negatively affects bone metabolism. Four-week-old male Wistar rats were randomly assigned to one of three groups for 4 wk: a zinc-adequate group (C, 30 ppm); a zinc-deficient group (ZD, 1 ppm); and a pair-fed group (PF, 30 ppm), which was pair-fed to the ZD group. Bone mineral density and bone mechanical properties were reduced in the ZD group compared to the C and PF groups. Compared with the C and PF groups, serum osteocalcin, a bone formation marker, was reduced in the ZD group. Conversely, urine deoxypyridinoline, a bone resorption marker, was increased in the ZD group compared to the C and PF groups. Calcium and phosphorus concentrations in bone were not different among all groups. The bone magnesium concentration was significantly higher in the ZD group than in the PF and C groups. Interestingly, compared with the C and PF groups, the ZD group showed a reduction in serum calcium concentration along with an increase in serum parathyroid hormone (PTH) concentration. Although serum 1,25-dihydroxycholecalciferol concentration was significantly higher in the ZD and PF groups than in the C group, the rate of apparent calcium absorption was significantly lower in the ZD group than in the C and PF groups. Therefore, zinc deficiency is suspected to cause an increase in serum PTH concentration owing to an inability to maintain calcium homeostasis, resulting in bone fragility.

Fibroblast growth factor 23 (FGF23) is a potent regulator of phosphorus (P) and vitamin D metabolism. Long-term dietary magnesium (Mg) deficiency increases circulating levels of FGF23, whereas the effects of short-term dietary Mg deficiency are unclear. Thus, the present study investigated whether short-term dietary Mg deficiency affects circulating levels of FGF23. We also assessed changes in renal mRNA expression of vitamin D metabolizing enzymes and type II sodium-phosphate (Na/Pi) cotransporters, since these are regulated by FGF23. Rats were fed a control diet (control group) or an Mg-deficient diet (Mg-deficient group) for 2, 4 or 7 days. Serum Mg levels were significantly lower in the Mg-deficient group than in the control group at all time points. Serum FGF23 levels were significantly higher in the Mg-deficient group than in the control group at day 7. The 25-hydroxyvitamin D-24-hydroxylase (24(OH)ase) mRNA levels were significantly higher in the Mg-deficient group than in the control group at day 7 . No significant differences in types IIa and IIc Na/Pi cotransporter mRNA levels were observed between the control and Mg-deficient groups. These results suggest that dietary Mg deficiency causes a rapid increase in circulating levels of FGF23 and renal 24(OH)ase mRNA levels.

In order to clarify the effects of a high-calcium (Ca) diet on bone formation in magnesium (Mg)-deficient rats, this study focused on the effects of a high-Ca diet on serum insulin-like growth factor-1 (IGF-1) levels. Male rats were randomized by weight into four groups, and fed one of four experimental diets containing two different Mg concentrations (0.05% (normal-Mg) or Mg-free (Mg-deficient)), and two different Ca concentrations (0.5% (normal-Ca) or 1.0% (high-Ca)) for 14 days. Serum concentrations of osteocalcin and IGF-1 were significantly lower in rats fed the Mg-deficient diet than in rats fed the normal-Mg diet. On the other hand, dietary Ca concentration had no significant influence on serum concentrations of osteocalcin and IGF-1. This study suggested that: 1) a high-Ca diet has no preventive effects on the decreased bone formation seen in Mg-deficient rats; and 2) a high-Ca diet does not enhance serum IGF-1 levels in Mg-deficient rats. Moreover, unchanged serum IGF-1 concentrations may contribute to the decreased bone formation seen in Mg-deficient rats receiving a high-Ca diet.

The effects of the dietary Ca and P ratio, independent of any vitamin D effects, on bone mineralization and turnover was examined in 60 VDRKO mice fed different Ca/P ratio diets. High dietary Ca/P ratio promoted bone mineralization and turnover with adequate intestinal Ca and P transports in VDRKO mice. Introduction: To clarify the effects of the dietary calcium (Ca) and phosphorus (P) ratio (Ca/P ratio) on bone mineralization and turnover in null-vitamin D signal condition, vitamin D receptor knockout (VDRKO) mice were given diets containing different Ca/P ratios. Materials and Methods: Five groups of 4-week-old VDRKO mice, 10 animals each, were fed diets for 4 weeks. Group 1 was wild-type littermate mice, fed the diet containing 0.5% Ca and P (Ca/P = 1). Group 2 was the control and was fed a similar diet (Ca/P = 1). Groups 3, 4, 5, and 6 were fed the following diets:0.5% Ca and 1.0% P (Ca/P = 0.5), 1.0% Ca and 1.0% P (Ca/P = 1), 1.0% Ca and 0.5% P (Ca/P = 2), and 0.5% Ca and 0.25% P (Ca/P = 2). Results and Conclusions: Compared with group 2, serum calcium and phosphorus levels in groups 4–6 significantly increased. Serum parathyroid hormone levels increased in group 3 and decreased in group 5. The amounts of intestinal calcium absorption decreased in groups 3 and 4. Phosphorus absorption increased in group 3 and decreased in groups 4–6. Bone mineral content (BMC) and bone mineral density (BMD) of the femur in group 3 significantly decreased and increased in group 5. In the primary spongiosa of the proximal tibia, the trabecular bone volume (BV/TV) and osteoid thickness (O.Th) in group 3 significantly increased, and decreased in group 6. In groups 5 and 6, the numbers of the trabecular osteoclasts increased. In groups 2 and 4, and the secondary spongiosa was identified in 5 of 10 mice. In group 3, there was no secondary spongiosa in either mouse. Osteoid maturation time (OMT) significantly decreased, and bone formation rate (BFR/BS) increased in groups 4–6. These data indicate that the dietary Ca/P ratio regulates bone mineralization and turnover by affecting the intestinal calcium and phosphorus transports in VDRKO mice. They may suggest the existence of Ca/P ratio-dependent, vitamin D-independent calcium and phosphorus transport system in the intestine.

The effects of various phosphate salts as the dietary phosphorus sources on the development of nephrocalcinosis and kidney function were examined in rats fed diets containing monophosphate salts (sodium dihydrogenphosphate, NaH2PO4, or potassium dihydrogenphosphate, KH2PO4) or polyphosphate salts (sodium tripolyphosphate, Na5P3O10, or potassium tripolyphosphate, K5P3O10), at levels representing normal phosphorus (normal phosphorus diet) or high phosphorus (high phosphorus diet) contents for 21 d. High phosphorus diet-feeding increased the kidney calcium and phosphorus concentrations. Kidney calcium and phosphorus concentrations were higher in rats fed the high phosphorus diet containing Na5P3O10 or K5P3O10 than in rats fed the high phosphorus diet containing NaH2PO4 or KH2PO4. Nephrocalcinosis was observed in all rats fed a high phosphorus diet, and the degree of nephrocalcinosis was more severe in rats fed Na5P3O10 or K5P3O10 than in rats fed NaH2PO4 or KH2PO4. In rats fed the high phosphorus diet, creatinine clearance was higher in rats fed Na5P3O10 or K5P3O10 than in rats fed NaH2PO4 or KH2PO4. In rats fed Na5P3O10 or K5P3O10, urinary albumin excretion and N-acetyl-beta-D-glucosaminidase (NAG) activity in the urine were increased in rats fed the high phosphorus diet. These were higher in rats fed the high phosphorus diet containing Na5P3O10 than in rats fed the high phosphorus diet containing NaH2PO4 or KH2PO4. This study observed that the development of nephrocalcinosis and kidney function in rats fed the high phosphorus diet was influenced by the difference in monophosphate or polyphosphate salts provided as the dietary phosphorus source, while the effects of sodium and potassium salts were not evident. We suggest that the development of nephrocalcinosis and kidney function in rats fed a high phosphorus diet was altered depending on the form of phosphate salts provided as the dietary source of phosphorus. Additionally, the development of nephrocalcinosis and diminished kidney function in rats fed the high phosphorus diet was more severe for polyphosphate salts as compared to monophosphate salts.

高濃度の食餌性リンを投与したラットにおける副甲状腺ホルモンの脱感作について検討を行ったところ, 血清中PTH濃度の上昇が観察されたにも関わらず, 血清中1α, 25 (OH) 2D3濃度の変化は観察されず, また尿中cAMP排泄量は有意に低値を示した。これは高リン食投与により分泌が維持されたPTHの作用が果たされずPTHの脱感作が観察された。また, PTHの作用部位であるPTH/PTHrP受容体mRNAが低下しており, 翻訳後のPTH/PTHrP受容体の量が減少していることが推察でき, PTHの脱感作が起きていることが推察された。

A magnesium (Mg) deficiency induces changes in calcium (Ca) and phosphorus (P) metabolism; however, the mechanisms responsible for these effects remain unclear. Since 1,25-dihydroxyvitamin D3 and type II sodium-phosphate (Na/Pi) cotransporters are essential regulators of Ca and P metabolism, this study examined the effects of Mg deficiency on the mRNA expression of vitamin D metabolizing enzymes (25-hydroxyvitamin D-1α-hydroxylase (1α(OH)ase) and 25-hydroxyvitamin D-24-hydroxylase (24(OH)ase)), and Na/Pi cotransporters (type IIa and IIc) in the rat kidney. Rats were divided into two groups and fed a control diet (Mg concentration: 0.05%) or a Mg-deficient diet (Mg concentration: Mg-free) for 21 days. 1α(OH)ase mRNA levels were significantly decreased in rats fed the Mg-deficient diet, while 24(OH)ase mRNA levels were significantly increased, compared to rats fed the control diet. Type IIa and IIc Na/Pi cotransporter mRNA levels in rats fed the Mg-deficient diet were significantly decreased compared to rats fed the control diet. These results suggest that Mg deficiency induces downregulation of 1α(OH)ase and type IIa and IIc Na/Pi cotransporters, and upregulation of 24(OH)ase in the kidney.

A magnesium (Mg)-deficient diet results in decreased serum phosphorus (P) levels and increased urinary P excretion; however, the mechanisms responsible for these effects are unclear. Fibroblast growth factor-23 (FGF-23) is a potent regulator of P homeostasis. To determine the mechanisms responsible for the change in serum levels and urinary excretion of P with Mg deficiency, the present study examined the effects of Mg deficiency on serum FGF-23 levels. Male rats were randomized by weight into two groups and fed a control diet (Mg concentration: 0.05%) or a Mg-deficient diet (Mg concentration: Mg-free) for 21 days. Serum P levels in rats fed the Mg-deficient diet were significantly lower than in rats fed the control diet. Furthermore, urinary P excretion was significantly higher in rats fed the Mg-deficient diet compared to rats fed the control diet. Conversely, the tubular reabsorption rate of P was significantly lower in rats fed the Mg-deficient diet than in the controls. Serum FGF-23 levels in rats fed the Mg-deficient diet were significantly higher than those in animals fed the control diet. The results from the present study indicate that 1) Mg deficiency increases serum FGF-23 levels; and 2) Mg deficiency causes increased urinary P excretion via inhibition of renal P reabsorption, resulting in a lowering of serum P levels. Moreover, we suggest that the high serum FGF-23 levels induced by Mg deficiency contribute to the decrease in renal P reabsorption.

Dietary intake of high levels of phosphorus is known to increase serum levels of parathyroid hormone (PTH); however, how this increased serum PTH affects the action of PTH in major target tissues, particularly by kidney, remains unknown. In the present study, we therefore undertook to clarify this point in intact animals fed a high-P diet by examining various parameters of PTH action. Twelve weanling Wistar male rats were assigned randomly to two groups: a control group with dietary Ca:P = 1:1 and a high-P group (Ca:P = 1:3) fed the standard AIN-76 diet supplemented with P (0.5 and 1.5 g/100 g of diet). After 3 weeks of feeding, in the high-P diet group, we observed that serum Ca was lowered, without a difference in serum P, when compared to the control group. Excretion of urinary cAMP, an index of renal PTH action, was also decreased, with higher excretion of urinary P in those rats fed the high-P diet. In agreement with the decreased cAMP excretion, a clear reduction in PTH/PTH-related protein (PTHrP) receptor gene expression as estimated by Northern blotting was observed in the kidney, despite increased levels of serum PTH. Thus, the present study indicated that a high-P diet reduces PTH action in the kidney, though the serum PTH is increased.

We evaluated the effect of magnesium supplementation on apparent calcium absorption, bone metabolism and dynamic bone strength in ovariectomized (OVX) rats as a model of postmenopausal women. Two groups of OVX rats were fed a 0.05% Mg diet or a 0.15% Mg diet, and one group of sham-operated rats was fed the 0.05% Mg diet for 42 d. We collected feces and urine of all rats for 3-d periods starting from d 3, 10, 17, 24, 31 and 38 of the feeding experiment for calcium and magnesium balance studies. Urine was collected for 24 h from d 41 of the feeding experiment for measuring deoxypyridinoline. After the 42 d, the rats were killed, serum prepared and femora excised. The apparent calcium absorption in the OVX rats fed 0.15% Mg was significantly lower than both other groups. Additionally, the urinary excretion of deoxypyridinoline (a bone resorption marker) and the serum parathyroid hormone level of the OVX rats fed the 0.15% Mg diet were significantly lower than in the OVX rats fed 0.05% Mg. Serum osteocalcin (a bone formation marker) in the OVX rats fed the 0.15% Mg diet was significantly higher than in the OVX rats fed 0.05% Mg. The breaking force and breaking energy of the femur in the OVX rats fed the 0.15% Mg diet were significantly higher than in the OVX rats fed the 0.05% Mg diet. These results indicate that magnesium supplementation reduces apparent calcium absorption, but promotes bone formation and prevents bone resorption in OVX rats. Moreover, our results indicate magnesium supplementation increases the dynamic strength of bone.

The effect of a magnesium-deficient diet on kidney function was studied in young male rats. The rats were fed a purified diet with a magnesium content of either 20.5 (control diet) or 2.6 mmol/kg (magnesium-deficient diet) for 21 d. In rats fed the magnesium-deficient diet, kidney wet and dry weights were significantly increased, and calcium and phosphorus concentrations in the kidney were significantly higher than in rats fed the control diet. Upon histological examination, an increase in the mesangial matrix of the glomeruli and injury to the brush border of the proximal tubules were observed in rats fed the magnesium-deficient diet. Also, a deposition of calcium was observed in the tubules of the corticomedullary junction and medulla of these rats. Total protein and albumin concentrations in serum were significantly decreased in rats fed the magnesium-deficient diet. Urinary albumin excretion was significantly higher, and N-acetyl-beta-D-glucosaminidase activity in the urine was significantly increased in rats fed the magnesium-deficient diet. These findings indicate diminished glomerular and proximal tubular functions. We suggest that a magnesium-deficient diet not only induces nephrocalcinosis, but it also diminishes kidney function.