Effect of vitamin K2 on cortical and cancellous bones in orchidectomized and/or sciatic neurectomized rats.

We examined the effect of vitamin K2 on cortical and cancellous bones in orchidectomized and/or sciatic neurectomized rats. Ninety male Sprague-Dawley rats, 3 months of age, were randomized by stratified weight method into nine groups with 10 rats in each group: baseline control (BLC), age-matched intact control (IN), IN+vitamin K2 administration (K), orchidectomy (ORX), ORX+K, unilateral sciatic neurectomy (NX), NX+K, ORX+NX (ONX), and ONX+K. Vitamin K2 (menatetrenone) was administered orally twice a week at a dose of 30 mg/kg each. After 10 weeks of feeding, the tibial shaft and proximal tibia were processed for cortical and cancellous bone histomorphometric analyses, respectively. An ORX-induced reduction in maturation-related cortical bone gain and ORX-induced cancellous bone loss were attributable to increased endocortical and trabecular bone turnover, respectively. NX- and ONX-induced reductions in maturation-related cortical bone gain were attributable to decreased periosteal bone formation and increased endocortical bone turnover, while NX- and ONX-induced cancellous bone loss was attributable to increased bone resorption and decreased bone formation. ORX-induced cancellous bone loss was more pronounced when combined with immobilization. Vitamin K2 administration did not significantly alter any parameters in IN rats. Vitamin K2 administration in ORX rats suppressed endocortical bone resorption and trabecular bone turnover, retarding a reduction in maturation-related cortical bone gain and cancellous bone loss. This effect on cancellous bone loss was primarily because of prevention of a reduction of trabecular thickness. Vitamin K2 administration in NX and ONX rats suppressed bone resorption and stimulated bone formation (mineralization), with retardation of a reduction of trabecular thickness without any significant effect on cancellous bone mass, and suppressed endocortical bone resorption, retarding a reduction in maturation-related cortical bone gain. The present study provides evidence indicating that vitamin K2 has the potential to suppress bone resorption or bone turnover and/or stimulate bone formation in vivo in ORX and/or NX rats.     

Possible mechanism of impaired calcium and vitamin D metabolism in nephrotic rats.

Patients who have nephrotic syndrome and normal renal function are hypocalcemic in spite of the elevated levels of serum parathyroid hormone (PTH) caused by a low serum concentration of 1,25-dihydroxyvitamin D[1,25(OH)2D], presumably because of its loss in urine. However, it has not been established whether the conversion of 25-hydroxyvitamin D[25(OH)D] into 1,25(OH)2D is impaired in the kidney. In this study, we examined the serum levels of vitamin D metabolites, and kinetics of renal 25(OH)D-1-hydroxylase activity in vitro, and nephrogenous cyclic AMP excretion in response to exogenous PTH administration in puromycin aminonucleoside-induced nephrosis in rats. Plasma ionized calcium and the serum levels of vitamin D metabolites were lower, and conversely, the serum PTH level was higher, in nephrotic rats than in controls. Serum 1,25(OH)2D levels were higher in 25(OH)D3-treated nephrotic rats than in untreated nephrotic rats, indicating that the low 1,25(OH)2D level in nephrotic rats is partially due to the low concentration of 25(OH)D. Although PTH levels were higher in nephrotic rats than in control rats, the Vmax of renal 25(OH)D-1-hydroxylase and nephrogenous adenosine 3',5'-monophosphate (cyclic AMP) excretion in response to exogenous PTH were significantly lower in nephrotic animals than in controls. These results suggest that abnormalities in calcium and vitamin D metabolism in nephrotic rats are partially attributable to impaired proximal tubular function.     

Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D.

Osteoblast activity and plasma 1,25(OH)2 vitamin D are increased in HPT but suppressed in HHM. To model HPT and HHM, we directly compared multiday continuous infusions of PTH versus PTHrP in humans. Continuous infusion of both PTH and PTHrP results in marked and prolonged suppression of bone formation; renal 1,25(OH)2D synthesis was stimulated effectively by PTH but poorly by PTHrP. INTRODUCTION: PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism (HPT) and humoral hypercalcemia of malignancy (HHM), respectively. Whereas HHM and HPT resemble one another in many respects, osteoblastic bone formation and plasma 1,25(OH)2 vitamin D are increased in HPT but reduced in HHM. MATERIALS AND METHODS: We performed 2- to 4-day continuous infusions of escalating doses of PTH and PTHrP in 61 healthy young adults, comparing the effects on serum calcium and phosphorus, renal calcium and phosphorus handling, 1,25(OH)2 vitamin D, endogenous PTH(1-84) concentrations, and plasma IGF-1 and markers of bone turnover. RESULTS: PTH and PTHrP induced comparable effects on renal calcium and phosphorus handling, and both stimulated IGF-1 and bone resorption similarly. Surprisingly, PTH was consistently more calcemic, reflecting a selectively greater increase in renal 1,25(OH)2 vitamin D production by PTH. Equally surprisingly, continuous infusion of both peptides markedly, continuously, and equivalently suppressed bone formation. CONCLUSIONS: PTHrP and PTH produce markedly different effects on 1,25(OH)2 vitamin D homeostasis in humans, leading to different calcemic responses. Moreover, both peptides produce profound suppression of bone formation over multiple days, contrasting with events in HPT, but mimicking HHM. These findings underscore the facts that the mechanisms underlying the anabolic skeletal response to PTH and PTHrP in humans is poorly understood, as are the signal transduction mechanisms that link the renal PTH receptor to 1,25(OH)2 vitamin D synthesis. These studies emphasize that much remains to be learned regarding the normal regulation of vitamin D metabolism and bone formation in response to PTH and PTHrP in humans.     

Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats.

The functional status and mechanism of increased VDR in GHS rats were investigated. Basal VDR and calbindins were increased in GHS rats. 1,25(OH)(2)D(3) increased VDR and calbindins in controls but not GHS rats. VDR half-life was prolonged in GHS rats. This study supports the mechanism and functional status of elevated VDR in GHS rats. INTRODUCTION: Genetic hypercalciuric stone-forming (GHS) rats form calcium kidney stones from hypercalciuria arising from increased intestinal calcium absorption and bone resorption and decreased renal calcium reabsorption. Normal serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels and increased vitamin D receptor (VDR) protein suggest that high rates of expression of vitamin D-responsive genes may mediate the hypercalciuria. The mechanism of elevated VDR and state of receptor function are not known. MATERIALS AND METHODS: GHS and non-stone-forming control (NC) male rats (mean, 249 g), fed a normal calcium diet, were injected intraperitoneally with 1,25(OH)2D3 (30 ng/100 g BW) or vehicle 24 h before cycloheximide (6 mg/100 g, IP) and were killed 0-8 h afterward. Duodenal VDR was measured by ELISA and Western blot, and duodenal and kidney calbindins (9 and 28 kDa) were measured by Western blots. RESULTS AND CONCLUSIONS: Duodenal VDR protein by Western blot was increased 2-fold in GHS versus NC rats (633 +/- 62 versus 388 +/- 48 fmol/mg protein, n = 4, p < 0.02), and 1,25(OH)2D3 increased VDR and calbindins (9 and 28 kDa) further in NC but not GHS rats. Duodenal VDR half-life was prolonged in GHS rats (2.59 +/- 0.2 versus 1.81 +/- 0.2 h, p < 0.001). 1,25(OH)2D3 prolonged duodenal VDR half-life in NC rats to that of untreated GHS rats (2.59 +/- 0.2 versus 2.83 +/- 0.3 h, not significant). This study supports the hypothesis that prolongation of VDR half-life increases VDR tissue levels and mediates increased VDR-regulated genes that result in hypercalciuria through actions on vitamin D-regulated calcium transport in intestine, bone, and kidney.     

Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency

Significant reduction in bone mineral density (BMD) occurs in patients with Parkinson's disease (PD), correlating with immobilization and with vitamin D deficiency, and increasing the risk of hip fracture, especially in elderly women. As a biological indicator of compromised vitamin K status, an increased serum concentration of undercarboxylated osteocalcin (Oc) has been associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women. We evaluated treatment with vitamin K(2) (menatetrenone; MK-4) in maintaining BMD and reducing the incidence of nonvertebral fractures in elderly female patients with PD. In a random and prospective study of PD patients, 60 received 45 mg of MK-4 daily for 12 months, and the remaining 60 (untreated group) did not. At baseline, patients of both groups showed vitamin D and K(1) deficiencies, high serum levels of ionized calcium, and glutaminic residue (Glu) Oc, and low levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1,25-(OH)(2)D and compensatory PTH secretion. BMD in the second metacarpals increased by 0.9% in the treated group and decreased by 4.3% in the untreated group (p < 0.0001). Vitamin K(2) level increased by 259.8% in the treated group. Correspondingly, significant decreases in Glu Oc and calcium were observed in the treated group, in association with an increase in both PTH and 1,25-(OH)(2)D. Ten patients sustained fractures (eight at the hip and two at other sites) in the untreated group, and one hip fracture occurred among treated patients (p = 0.0082; odds ratio = 11.5). The treatment with MK-4 can increase the BMD of vitamin D- and K-deficient bone by increasing vitamin K concentration, and it can also decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1,25-(OH)(2)D concentration.     

Evidence that obesity does not influence the vitamin D-endocrine system in blacks

As compared to nonobese white men and women, age-matched nonobese black subjects and obese white individuals show alterations in the vitamin D-endocrine system that are characterized by increases in mean serum immunoreactive parathyroid hormone (PTH), serum 1,25-dihydroxyvitamin D [1,25-(OH)2D], and urinary cyclic adenosine 3,5-monophosphate (cAMP) and by decreases in mean serum 25-hydroxyvitamin D (25 OHD) and in urinary calcium. Thus, both groups show secondary hyperparathyroidism which is associated with increased renal tubular reabsorption of calcium and increased renal synthesis of 1,25-(OH)2D. In view of these findings, studies were conducted in 10 obese black subjects (3 men and 7 women) and in 12 nonobese black individuals (7 men and 5 women), ranging in age from 20 to 35 yr, to determine whether obesity influences the vitamin D-endocrine system in blacks. Body weight averaged 99 +/- 4 kg in the obese and 73 +/- 3 kg in the nonobese subjects (p less than .001). All of them were hospitalized on a metabolic ward and were given a constant daily diet containing 400 mg of calcium, 900 mg of phosphorus, 110 meq of sodium, 65 meq of potassium, and 18 meq of magnesium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Is there a differential response to alfacalcidol and vitamin D in the treatment of osteoporosis?

There is a decline in serum 25 hydroxyvitamin D (25OHD), 1,25 dihydroxyvitamin D (1,25(OH)₂D), and calcium absorption with advancing age, which may lead to secondary hyperparathyroidism and bone loss. Studies show a relationship between serum 25OHD and bone density in older men and women, with an inverse correlation between bone density and parathyroid hormone (PTH). Vitamin D supplementation in this age group improves calcium absorption, suppresses PTH, and decreases bone loss. Vitamin D many also reduce the incidence of hip and other nonvertebral fractures, particularly in the frail elderly who are likely to have vitamin D deficiency. Patients with established vertebral osteoporosis have lower calcium absorption than age-matched control subjects, possibly due to reduced serum 1,25(OH)₂D or to relative resistance to the action of vitamin D on the bowel. Malabsorption of calcium in women with vertebral crush fractures does not usually respond to treatment with physiological doses of vitamin D, but can be corrected by pharmacological doses of vitamin D or by low doses of calcitriol or alfacalcidol. In a recent randomized, controlled study in 46 elderly women with radiological evidence of vertebral osteoporosis, alfacalcidol 0.25 μg twice daily improved calcium absorption, decreased serum PTH, and reduced alkaline phosphatase, whereas vitamin D₂ 500–1000 IU daily had no effect over the 6-month study period. Studies of the effect of the vitamin D metabolites in the management of elderly women with established vertebral osteoporosis have yielded conflicting results, but suggest that alfacalcidol and calcitriol may decrease spinal bone loss and reduce the incidence of vertebral fractures. Although vitamin D supplementation decreases bone loss and fracture risk in the frail elderly, vitamin D metabolites may prove more useful in the treatment of elderly women with vertebral osteoporosis.     

Vitamin D and calcium receptors: links to hypercalciuria

PURPOSE OF REVIEW: In idiopathic hypercalciuria, patients have increased intestinal Ca absorption and decreased renal Ca reabsorption, with either elevated or normal serum levels of 1,25-dihydroxyvitamin D. As 1,25-dihydroxyvitamin D exerts its biologic effects through interactions with the vitamin D receptor, we examine the actions of this receptor and 1,25-dihydroxyvitamin D in animals with genetic hypercalciuria. RECENT FINDINGS: In genetic hypercalciuric stone-forming rats intestinal calcium transport is increased and renal calcium reabsorption is reduced, yet serum 1,25-dihydroxyvitamin D levels are normal. Elevated intestinal and kidney vitamin D receptors suggest that increased tissue 1,25-dihydroxyvitamin D-vitamin D receptor complexes enhance 1,25-dihydroxyvitamin D actions on intestine and kidney, and vitamin D-dependent over-expression of renal calcium-sensing receptor alone can decrease tubule calcium reabsorption. In TRPV5-knockout mice, ablation of the renal calcium-influx channel decreases tubular calcium reabsorption, and secondary elevations in 1,25-dihydroxyvitamin D increase intestinal calcium transport. SUMMARY: 1,25-Dihydroxyvitamin D or vitamin D receptor may change intestinal and renal epithelial calcium transport simultaneously or calcium-transport changes across renal epithelia may be primary with a vitamin D-mediated secondary increase in intestinal transport. The extent of homology between the animal models and human idiopathic hypercalciuria remains to be determined.     

New vitamin D analogs

BACKGROUND: 1,25-(OH)2D3 (calcitriol) controls parathyroid gland growth and suppresses the synthesis and secretion of parathyroid hormone. Because of this, 1,25-(OH)2D3 has been used successfully for the treatment of secondary hyperparathyroidism, which almost always accompanies renal failure. However, the potent effect of 1,25-(OH)2D3 on intestinal calcium and phosphorus absorption and bone mineral mobilization often leads to the development of hypercalcemia and hyperphosphatemia precluding 1,25-(OH)2D3 therapy. METHODS: This has led to the development of vitamin D analogs that retain the suppressive action on PTH and parathyroid gland growth, but that have less calcemic and phosphatemic activity. Currently, two analogs, 19-nor-1,25-(OH)2D2 and 1,alpha(OH)D2, are being used for the treatment of secondary hyperparathyroidism in the United States, and two are being used in Japan, 22-oxa-calcitriol and 1,25-(OH)2-26,27F6 D3. RESULTS: All four analogs suppressed PTH, but had less calcemic and phosphatemic activity than 1,25-(OH)2D3. In rats, 19-nor-1,25-(OH)2D2 has been shown to be less calcemic and phosphatemic compared to 1,alpha(OH)D2. CONCLUSION: Therapeutic doses of 19-nor-1,25-(OH)2D2 could produce a lower Ca x P product compared to 1,alpha(OH)D2, which could be an important consideration in patient treatment. Further studies are necessary to define these differences and to understand the mechanisms behind the differential actions of vitamin D analogs.     

Efficacy of 19-Nor-1,25-(OH)2D2 in the prevention and treatment of hyperparathyroid bone disease in experimental uremia

BACKGROUND: The control of parathyroid hyperplasia and high circulating parathyroid hormone (PTH) levels is crucial in preventing secondary hyperparathyroidism (SH) in renal failure. Parathyroid gland enlargement and elevated levels of PTH are major contributors to increase bone resorption, a feature of renal osteodystrophy. METHODS: These studies assessed the efficacy of the 1,25(OH)2D3 analog, 19-Nor-1,25(OH)2D2 (19-Nor), in the prevention (protocol I) and treatment (protocol II) of SH and renal osteodystrophy in uremic rats. In protocol I, normal and uremic rats were fed a high phosphorus diet for 2 months; uremic rats were administered intraperitoneal injections of either vehicle or 19-Nor (200 ng three times a week). In protocol II, normal and uremic rats were fed a high phosphorus diet for 4 months; 2 months after the onset of uremia, rats were administered either intraperitoneal vehicle or 19-Nor (200 ng three times a week). Serum PTH and bone histology were used to assess the degree of SH. RESULTS: 19-Nor was effective in preventing (protocol I) and suppressing (protocol II) the significant SH induced by uremia and further enhanced by a high phosphorus diet. In protocol I, bone histology in uremic controls showed a threefold increase in the cancellous bone mass compared to normal rats. This expansion in unmineralized bone was accompanied by 5-, 1.5-, and 7-fold increases in eroded surface, mineralization lag time (MLT), and bone formation rate (BFR/BS), respectively. Moreover, cortical bone porosity in untreated uremic rats increased 267-fold compared to normal animals. 19-Nor ameliorated these changes in cancellous and cortical bone. In protocol II, the reported indices worsened even further. In contrast, 2 months of 19-Nor treatment improved bone histology by reducing cortical bone porosity, woven bone formation, MLT, and BFR/BS. CONCLUSION: In an experimental model of chronic renal failure (CRF), 19-Nor prevents SH and ameliorates the histomorphometric changes induced by uremia and high phosphorus diet. In addition, 19-Nor suppresses serum PTH and improves bone histology in uremic rats with established severe SH. Further studies in patients with CRF are necessary to define the clinical applicability of 19-Nor on bone histology in humans.     

Renal mass and reserve of vitamin D: determinants in primary hyperparathyroidism

We studied circulating 1,25(OH)2D3 and its determinants in 102 patients with primary hyperparathyroidism (PHPT), 33 of them with recurrent renal stones, 60 with non-specific symptoms, and nine with overt bone disease. Means for serum 1,25(OH)2D3 and intestinal absorption of calcium were abnormally high in the renal stone group, slightly elevated in the non-specific group, and low-normal in the bone disease group. In the whole population of patients, we found a positive correlation between circulating 1,25(OH)2D3 and creatinine clearance (taken as an index of the functional renal mass). Negative correlations were observed between 1,25(OH)2D3 and age, and between creatinine clearance and age, the latter being not different from that observed in a normal large population. In the renal stone group, means for the determinants of the renal 1 alpha hydroxylase activity, that is, PTH activity expressed as nephrogenous cyclic AMP (NcAMP), serum phosphate and calcium were identical to those of the group with non-specific symptoms. However means for age were lower and functional renal mass significantly higher in the renal stone group, which may account for the higher value of circulating 1,25(OH)2D3. In the bone disease group, means for age, renal mass and serum calcium were identical to those of the group with non-specific symptoms, and NcAMP was far higher and hypophosphatemia more marked, which may not account for the lower value of circulating 1,25(OH)2D3. However, in the bone disease group, serum 25(OH)D was abnormally low, which may limit the renal production of 1,25(OH)2D3 and explain the low-normal circulating values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relative effectiveness of vitamin D metabolites in increasing bone mineral solubility

Weanling rats were given a vitamin D-deficient diet containing 1.4% calcium and 1.0% phosphorus. After 4 weeks these deficient animals were injected for 7 days with selected doses of one of the following vitamin D metabolites: 25(OH)D3, 1,25(OH)2D3, 24,25(OH)2D3, 25,26(OH)2D3 or the ethanol vehicle. A vitamin D-replete group was placed on the same diet but injected with 50 IU of vitamin D3 once a week for the entire 5-week period. By the use of a modified Ussing chamber [1], the measurements of calcium fluxes into and from the rat calvaria were possible. These data enabled the apparent mineral solubilities to be derived. After 5 weeks on this diet the vitamin D-deficient rats had low levels of serum calcium (1.41 mM) and decreased mineral solubility when compared to the vitamin D-replete group. The apparent solubility of the bone mineral increased toward the vitamin D-replete level in calvaria from vitamin D metabolite-treated rats. However, these changes did not directly reflect the alterations in the level of serum calcium. At any given dose level, 1,25(OH)2D3 was the most effective metabolite in increasing serum calcium. In fact, the high dose (250 pmoles/day) was hypercalcemic. Next in effectiveness was 25(OH)D3. These two metabolites were equally effective in increasing mineral solubility. At a 10 times higher dose, the 24,25(OH)2D3 metabolite was able to normalize serum calcium and improve but not normalize mineral solubility. At the high dose (260 pmoles/day), the 25,26(OH)2D3 metabolite caused no effect on mineral solubility and minimal increases in serum calcium.     

Differential effect of caffeine administration on calcium and vitamin D metabolism in young and adult rats

Since coffee drinking may lead to a worsening of calcium balance in humans, we studied the serial changes of serum calcium, PTH, 1,25-dihydroxyvitamin D (1,25(OH)2D) and calcium balance in young and adult rats after daily administration of caffeine for 4 weeks. In the young rats, there was an increase in urinary calcium and endogenous fecal calcium excretion after four days of caffeine administration that persisted for the duration of the experiment. Serum calcium decreased on the fourth day of caffeine administration and then returned to control levels. In contrast, the serum PTH and 1,25(OH)2D remained unchanged initially, but increased after 2 weeks of caffeine administration. The intestinal absorption coefficient of calcium remained unchanged, instead of declining gradually as observed in the young control group. This finding suggests that the intestinal absorption of calcium was stimulated by the increase in 1,25(OH)2D production after chronic administration of caffeine. In the adult rat group, an increase in the urinary calcium and endogenous fecal calcium excretion and serum levels of PTH was found after caffeine administration. However, the serum 1,25(OH)2D levels and intestinal absorption coefficient of calcium remained the same as in the adult control group. A decrease in the net balance of calcium occurred as a result of increased calcium excretion. The current study, using an animal model, supports the suggestion that chronic administration of caffeine could lead to negative calcium balance when there is an impaired ability to increase the efficiency of calcium absorption. Such a situation exists in elderly human subjects, since they have a reduced capacity to synthesize 1,25(OH)2D.     

Regulation of intestinal vitamin D receptor expression in experimental uraemia: effects of parathyroidectomy and administration of PTH

In this study, the effects of PTH on binding of [³H]-1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and on vitamin D receptor (VDR) mRNA concentration were assessed in intestinal mucosa of subtotally nephrectomized rats (Nx) and in intestinal mucosa sham-operated rats with normal kidney function (Intact). Intestinal 1,25(OH)2D3 binding capacity of Intact remained unchanged (I) after parathyroidectomy (PTx), (ii) after administration of PTH for up to 6 days, and (iii) after PTx and subsequent administration of PTH (n=4 experiments). In contrast, PTx of subtotally nephrectomized animals (Nx-PTx) decreased 1,25(OH)2D3 binding capacity from 757±95 fmol/mg protein in Nx to 417±42 in Nx-PTx (P<0.01, n=5). PTH administration had no effect on intestinal 1,25(OH)2D3 binding capacity in Nx. However, PTH administration to Nx-PTx resulted in re-elevation of 1,25(OH)2D3 binding capacity to a level (790±113 fmol/mg protein) which was comparable to Nx. Kd-values remained unaltered under all experimental conditions. The intestinal VDR mRNA concentration (normalized to {beta}-actin mRNA) was decreased, on average, by 23% in Nx-PTx (P<0.05 versus Nx). In further experiments, 1,25(OH)2D3 was administered to Nx-PTx. This resulted in upregulation of 1,25(OH)2D3 binding capacity as compared to vehicle-treated Nx-PTx (562±90 fmol/mg protein versus 249±32, P<0.01). The latter results could indicate that PTH-mediated stimulation of residual renal 1,25(OH)2D3 production was involved in PTH-mediated up-regulation of intestinal 1,25(OH)2D3 binding capacity in Nx-PTx. To rule out this possibility, PTH was administered to totally nephrectomized and parathyroidectomized rats (TNx-PTx). Since PTH caused an approximately 80% increase (P<0.05) in intestinal 1,25(OH)2D3 binding capacity under those experimental conditions a mediator role of 1,25(OH)2D3 could be excluded. Functional significance of decreased intestinal 1,25(OH)2D36 binding capacity in Nx-PTx as compared to Nx was demonstrated by significantly lower 1,25(OH)2D3-mediated stimulation of intestinal 25(OH)2D3-24-hydroxylase activity in Nx-PTx (209±68 pmol/mg protein) than in Nx (385±81, P<0.01). The modulation of intestinal 1,25(OH)2D3 binding capacity was not correlated with changes in calcium, phosphate or 1,25(OH)2D3 serum concentrations under our experimental conditions. Taken together, intact parathyroid gland function was required to maintain adequate intestinal VDR expression in experimental uraemia (but not in normal animals). The mechanism of the modulation of intestinal VDR by PTH remains to be elucidated although an indirect effect of PTH on VDR expression in intestinal mucosa seems most likely.     

Effect of 2-methylene-19-nor-(20S)-1 alpha-hydroxy-bishomopregnacalciferol (2MbisP), an analog of vitamin D, on secondary hyperparathyroidism.

Vitamin D analogs are being developed that retain therapeutic effects but are less calcemic and phosphatemic, a concern in CKD patients who are prone to vascular calcification. We tested a new analog of vitamin D, 2MbisP, and found that it suppresses PTH at doses that do not affect serum Ca or P. INTRODUCTION: Calcitriol is used for the treatment of secondary hyperparathyroidism. However, its use is often limited by the development of hypercalcemia and hyperphosphatemia, an important consideration in patients with chronic kidney disease (CKD) because they are prone to vascular calcification. To minimize this toxicity, structural modifications in the vitamin D molecule have led to the development of calcitriol analogs with selective actions. MATERIALS AND METHODS: In this study, we compared the effects of 1,25(OH)(2)D(3) and a new analog, 2-methylene-19-nor-(20S)-1 alpha-hydroxy-bishomopregnacalciferol (2MbisP), on the development of secondary hyperparathyroidism and established secondary hyperparathyroidism in uremic rats and on mobilization of calcium and phosphorus from bone in parathyroidectomized rats. The clearance from circulation, half-life, and binding affinities to the vitamin D-binding protein and vitamin D receptor of this compound were also evaluated. RESULTS: Uremia produced a marked rise in plasma PTH, but treatment every other day for 2 wk with either 1,25(OH)(2)D(3) (4 ng) or 2MbisP (250, 750, 1500, or 3000 ng) suppressed this increase by >50%. The suppression by 1,25(OH)(2)D(3), however, was accompanied by increases in ionized calcium, phosphorus, and the calcium x phosphorus product, whereas these three parameters were unchanged by 2MbisP. The binding affinity of 2MbisP was 10-20 times less for the vitamin D receptor and 1000 times less for the serum vitamin D-binding protein compared with 1,25(OH)(2)D(3). Also, 2MbisP was cleared more rapidly from the circulation (t1/2 = 10 min) than 1,25-(OH)(2)D(3) (t1/2=7-9 h). In parathyroidectomized rats fed calcium-or phosphorus-deficient diets, daily injections of 2MbisP (1500 or 3000 ng), unlike 1,25(OH)(2)D(3) (50 ng), had no effect on calcium or phosphorus mobilization from bone. CONCLUSIONS: In uremic rats, 2MbisP can suppress PTH at doses that do not affect plasma calcium, phosphorus, and calcium x phosphorus product. This new vitamin D analog may represent an important tool in the treatment of secondary hyperparathyroidism in patients with CKD.     

An investigation of calcium intake, 1-alpha(OH)D3, and etidronate on bone

The synthetic metabolite of vitamin D3 [1 alpha(OH)D3] caused a significant plasma calcium elevation in rats only when dietary calcium was low. Animals given the low calcium diet (0.005%) had lower plasma parathyroid hormone (PTH) levels when the diet contained 1 alpha(OH)D3 and significantly higher levels than animals on a high calcium (0.95%) diet, with or without the vitamin. The nutritional stress of a low calcium diet without 1 alpha(OH)D3 resulted in a prolonged severe hypocalcemia and elevated serum PTH levels. A higher ash, phosphate, and calcium content was found in the bones of animals fed the high calcium diet, with no vitamin D3 that were given etidronate (EHDP). When animals received the same calcium diet with 1 alpha(OH)D3 supplementation, EHDP administration increased the percentage of bone ash but had no effect on ash weight. 1 alpha(OH)D3 or EHDP did not affect ash weight, dry fat free weight, and percentage of ash of bone of animals receiving a low calcium diet. The percentage of calcium and phosphorus in bone ash was similar among all groups, although the amounts per humerus were characteristically related to the calcium intake. There was approximately 20-25% less bone mineral and calcium and phosphorus in the humeri of low calcium intake animals than in animals provided an adequate dietary calcium.