Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men

CONTEXT: Fibroblast growth factor 23 (FGF-23) is important in the regulation of phosphorus and vitamin D metabolism. States of excess circulating FGF-23 are associated with renal phosphate wasting and inappropriately low serum 1,25-dihydroxyvitamin D [1,25(OH)(2)D] concentrations. Conversely, states of absent or biologically inactive circulating FGF-23 are associated with increased serum phosphorus and 1,25(OH)(2)D concentrations. Restriction of the dietary intake of phosphorus increases renal phosphate reabsorption and 1,25(OH)(2)D production, whereas the opposite occurs when dietary phosphorus is supplemented. OBJECTIVE: We sought to determine whether serum FGF-23 concentration is regulated by dietary phosphorus and thereby mediates the physiological response of serum 1,25(OH)(2)D to changes in dietary phosphorus. DESIGN, SETTING, AND PARTICIPANTS: We studied 13 healthy men as inpatients during a 4-wk dietary phosphorus intervention study. INTERVENTION: Subjects consumed a constant diet that provided 500 mg of phosphorus per day, which was supplemented to achieve three phosphorus intakes, each of 9 d: 1) control = 1500 mg/d; 2) supplemented = 2300 mg/d; 3) restricted = 625 mg/d. Intakes of calcium, sodium, potassium, magnesium, and energy were constant. MAIN OUTCOME MEASURE: Serum FGF-23, 1,25(OH)(2)D, phosphorus, and calcium concentrations were measured. RESULTS: Serum FGF-23 concentrations decreased significantly from 30.7 +/- 8.7 pg/ml during phosphorus supplementation to 19.6 +/- 7.0 pg/ml during phosphorus restriction. Serum 1,25(OH)(2)D concentrations increased significantly from 29 +/- 10 pg/ml (75 +/- 26 pmol/liter) during phosphorus supplementation to 40 +/- 16 pg/ml (104 +/- 42 pmol/liter) during phosphorus restriction (P < 0.001). Serum 1,25(OH)(2)D concentrations varied inversely with those of serum FGF-23 (r = -0.67, P < 0.001). CONCLUSIONS: We conclude that in healthy men, changes in dietary phosphorus within the physiological range of intakes regulate serum FGF-23 concentrations and suggest that dietary phosphorus regulation of 1,25(OH)(2)D production is mediated, at least in part, by changes in circulating FGF-23.     

Regulatory mechanisms of circulating fibroblast growth factor 23 in parathyroid diseases

Fibroblast growth factor-23 (FGF-23) is a circulating factor regulating phosphate and vitamin D homeostasis. Phosphate intake and an administration of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) increase circulating FGF-23 levels, and elevated FGF-23 prevents hyperphosphatemia and vitamin D toxicity by hyperphosphaturia and suppression of circulating 1,25(OH)(2)D level, comprising a feedback loop to maintain phosphate and vitamin D homeostasis. Excess secretion of parathyroid hormone (PTH), another phosphaturic factor, elevates the serum calcium level in primary hyperparathyroidism. PTH also elevates circulating FGF-23 level, which cooperatively enhances the phosphaturia, resulting in hypophosphatemia. The circulating FGF-23 level increases as renal function declines in chronic kidney disease (CKD), and it exhibits significant and positive correlations with serum phosphate, calcium, and PTH in CKD patients on maintenance hemodialysis, suggesting that these parameters regulate circulating FGF-23 level. Tight associations between circulating FGF-23 and calcium levels were observed both in patients with primary hyperparathyroidism and in CKD patients on maintenance hemodialysis, suggesting the role of serum calcium on FGF-23 regulatory mechanisms. FGF-23 may have a physiological role in preventing tissue damage such as ectopic calcifications, partly via suppressing the serum calcium x phosphate product by accelerating urinary phosphate excretion and suppressing vitamin D activation.     

Fibroblast growth factor-23 in patients with Graves' disease before and after antithyroid therapy: its important role in serum phosphate regulation

OBJECTIVE: Hyperthyroidism is a well-described cause of hyperphosphatemia. We aimed to clarify the physiological role of fibroblast growth factor (FGF)-23 in serum phosphate homeostasis in patients with Graves' disease during the course of treatment for hyperthyroidism. CONTEXT: The study group comprised 56 patients (45 for a cross-sectional study and 11 for a longitudinal study) with Graves' disease. For the cross-sectional study, patients were assigned, on the basis of their serum phosphate level, to a hypophosphatemia group (n = 14), a normophosphatemia group (n = 16), or a hyperphosphatemia group (n = 15). Serum FGF-23, calcium, phosphate, PTH, and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were compared between the three groups. For the longitudinal study, we assessed changes in these biochemical indices before and after antithyroid treatment. RESULTS: In the cross-sectional study, the serum FGF-23 level was significantly higher (P < 0.05) in the hyperphosphatemia group than in the other groups (61 +/- 36 ng/liter vs. 31 +/- 22 ng/liter and 30 +/- 9 ng/liter). In the longitudinal study, serum levels of FGF-23 decreased significantly (P < 0.05) from a high of 54 +/- 12 ng/liter before treatment to 29 +/- 14 ng/liter after treatment. In contrast, the serum 1,25(OH)(2)D level increased significantly (P < 0.005) from 55 +/- 22 pmol/liter before treatment to 185 +/- 76 pmol/liter 3 months after treatment. Serum FGF-23 levels were positively correlated with serum phosphate levels (P < 0.0001) and negatively correlated with serum 1,25(OH)(2)D levels (P < 0.0001). CONCLUSIONS: The significant positive correlation between serum levels of phosphate and FGF-23 indicates that FGF-23 may play an important role in serum phosphate homeostasis by its up-regulation in the hyperphosphatemic condition.     

Influence of renal function on clinico-pathological features of primary hyperparathyroidism

OBJECTIVE: Disturbed renal function may play an important role in the clinico-pathological presentation of primary hyperparathyroidism (pHPT). We studied the influence of renal function on the clinico-pathological characteristics of 141 patients (123 women and 18 men) with surgically proven pHPT. METHODS: The 141 patients were assigned to one of two groups based on creatinine clearance (C(cr)) level: a renal insufficiency group (n=37) in which C(cr) of patients was <70 ml/min and a normal renal function group (n=104) in which C(cr) was > or =70 ml/min. Clinical presentation and biochemical indices were evaluated and compared between the two groups. RESULTS: Age, and frequency of hypertension and of diabetes mellitus were significantly (P<0.001, P<0.05 and P<0.05 respectively) higher in the renal insufficiency group than in the normal renal function group. Serum levels of calcium, intact parathyroid hormone and bone Gla protein were significantly (P<0.05) higher and the excised parathyroid weighed significantly more (P<0.05) in the renal insufficiency group than in the normal renal function group; however, serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and 24 h urinary calcium excretion were significantly (P<0.001 and P<0.05 respectively) lower in the former than in the latter group. There was a significant inverse correlation between C(cr) level and serum calcium (r=0.315, P<0.001) and a significant positive correlation between C(cr) level, 1,25(OH)(2)D (r=0.315, P<0.001), and 24 h calcium excretion (r=0.458, P<0.0001). CONCLUSIONS: Clinico-pathological features of pHPT were notably influenced by even moderate renal insufficiency. Urinary calcium excretion decreased according to the decrease in glomerular filtration rate. Therefore, endocrinologists need to appraise urinary calcium excretion and renal function of pHPT patients when considering surgery or in discriminating familial hypocalciuric hypercalcemia.     

Vitamin D status affects osteopenia in postmenopausal patients with primary hyperparathyroidism

Controversy still exists about whether vitamin D status is related to the severity of primary hyperparathyroidism (pHPT), although vitamin D insufficiency is frequent in pHPT. The present study was therefore performed to examine the relationships between vitamin D status and various parameters in 30 postmenopausal pHPT patients. BMD values were measured by dual-energy x-ray absorptiometry at the lumbar spine (L(2-4)), femoral neck (FN) and distal one third of the radius (Rad 1/3). Serum levels of 25 hydroxy-vitamin D(3) [25(OH)D] and 1,25-dihydroxy vitamin D(3) [1,25(OH) (2)D(3)] were 15.8 +/- 3.5 microg/l and 69.3 +/- 33.3 ng/l in pHPT patients, respectively. Serum levels of calcium and PTH seemed to be negatively correlated to serum 25(OH)D levels, although the differences were not significant. However, when subjects with the highest serum PTH levels (PTH>1000 pg/ml) were excluded from the analysis, the correlation was significant between serum 25(OH)D levels and PTH, indicating that vitamin D status affects the severity of pHPT when severe cases were excluded. In addition, serum levels of 1,25(OH)(2)D(3) were significantly and negatively correlated to serum 25(OH)D levels. On the other hand, serum levels of 25(OH)D were significantly and positively correlated to BMD (Z-score) at the lumbar spine, but not at the radius and femoral neck; however, serum 25(OH)D levels were not correlated to the levels of any bone metabolic indices measured. Moreover, serum levels of 25(OH)D were not related to urinary calcium and the tubular reabsorption rate of phosphorus, and they were similar in groups with and without renal stones. In conclusion, vitamin D status seemed to be related to the severity of disease in postmenopausal patients with pHPT. In particular, the relationship between serum 25(OH)D level and BMD at the lumbar spine was predominant.     

Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men

The renal handling of inorganic phosphate (Pi) is controlled not only by PTH, but also by hitherto undetermined mechanisms dependent on phosphate intake. Recently, fibroblast growth factor (FGF)-23 was identified as a novel phosphaturic factor in tumor-induced osteomalacia and autosomal-dominant hypophosphatemic rickets. We hypothesized that phosphate intake could influence FGF-23 concomitantly to the changes in renal Pi handling. Twenty-nine healthy males were subjected to a 5-d low-phosphate diet and a phosphate binder, followed by a high-phosphate diet including supplements. Concomitant modifications in calcium intake allowed minimizing PTH changes in response to dietary phosphate. Serum FGF-23 levels significantly decreased on the low-phosphate diet, then increased with the oral phosphate load. Changes in FGF-23 were positively correlated with changes in 24-h urinary Pi excretion and negatively correlated with changes in the maximal tubular reabsorption of Pi and 1,25(OH)(2)D(3) (calcitriol), whereas PTH was not. In multivariate analysis, changes in FGF-23 remained the most significantly correlated to changes in 1,25(OH)(2)D(3) and maximal tubular reabsorption of Pi. Moreover, FGF-23 was positively correlated to serum osteocalcin, a marker of osteoblastic activity. In summary, FGF-23 was inversely related to renal Pi transport and serum calcitriol levels in healthy young men. These data suggest that FGF-23 may be implicated in the physiological regulation of Pi homeostasis in response to dietary phosphate changes, independent of PTH.     

Plasma 1,25-dihydroxyvitamin D levels in primary hyperparathyroidism depend on sex, body mass index, plasma phosphate and renal function

BACKGROUND: Primary hyperparathyroidism (PHPT) is characterized by elevated plasma levels of PTH and calcium with reduced plasma phosphate. Physiologically, renal 1alpha,25-dihydroxyvitamin D [1,25(OH)(2)D] production is stimulated by PTH and phosphate deprivation, and inhibited by 1,25(OH)(2)D itself and calcium. AIM: To investigate relations between circulating levels of 1,25(OH)(2)D, 25-dihydroxyvitamin D (25OHD), PTH, calcium, phosphate, renal function and skeletal complications in patients with PHPT. DESIGN: Cross-sectional study. MATERIAL: Two hundred and fifty-two consecutive hypercalcaemic Caucasian patients aged 24-91 (median 65.9) years (85.3% females) with PHPT. RESULTS: In patients with PHPT, plasma 1,25(OH)(2)D was increased by 27%[107 (9-250) pmol/l, median (range)] compared to controls [84 (18-172) pmol/l, P < 0.001]. In univariate models, plasma 1,25(OH)(2)D depended inversely on age (r = -0.23, P < 0.001) and plasma phosphate (r = -0.23, P < 0.001) and positively on plasma calcium (r = 0.14, P < 0.05), plasma 25OHD (r = 0,15, P < 0.05) and creatinine clearance rate (r = 0.32, P < 0.001). In the final multiple regression model, plasma 1,25(OH)(2)D depended positively on renal function (r(p) = 0.43, P < 0.001) and female sex (r(p) = 0.15, P < 0.05) but inversely on body mass index (BMI; r(p) = -0.23, P < 0.005) and plasma phosphate (r(p) = -0.18, P < 0.05). Plasma 1,25(OH)(2)D correlated positively with renal calcium excretion and inversely with lumbar spine bone mineral density (BMD) but was not associated with risk of fractures or renal stones. CONCLUSION: Patients with PHPT have elevated plasma 1,25(OH)(2)D levels but, to a large extent, individual values overlap controls. The increase in plasma 1,25(OH)(2)D depends on renal function, hypophosphataemia and the female sex and is attenuated by high BMI. High plasma 1,25(OH)(2)D is associated with higher plasma calcium levels.     

The adaptation and relationship of FGF-23 to changes in mineral metabolism in Graves' disease

OBJECTIVE: The aim of this study was to observe the changes in bone and mineral metabolism and to confirm the regulation of fibroblast growth factor-23 (FGF-23) in untreated Graves' disease. PATIENTS AND MEASUREMENTS: The study comprised 39 patients, with or without Graves' disease. The Graves' disease group was made up of 21 newly diagnosed patients, enrolled before starting treatment. Their disease was determined by biochemical and radiological means. The control group was composed of 18 people who were proven to be euthyroid without any diseases affecting bone and mineral metabolism. FGF-23, calcium, phosphate, PTH, 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels and bone turnover markers were compared between these groups. RESULTS: Serum calcium and phosphate, plasma FGF-23 and free T4 were significantly higher in the Graves' disease group than in the healthy control group (P < 0.05). The bone turnover markers serum osteocalcin and C-terminal cross-linked telopeptide of type 1 collagen (s-CTx) were also significantly elevated in the Graves' disease group, and had a positive correlation with free T4 levels. However, there was no significant decrease in PTH and 1,25(OH)2D in the Graves' disease group. Plasma levels of FGF-23 exhibited a positive correlation with serum phosphate levels and with free T4 levels (P < 0.05). CONCLUSIONS: These findings suggest that FGF-23 is physiologically related to serum phosphate homeostasis, as indicated indirectly by the changes in bone and mineral metabolism, in untreated Graves' disease.     

Elevated serum parathyroid hormone concentration in eucalcemic patients after parathyroidectomy for primary hyperparathyroidism and its relationship to vitamin D profile

Elevation of serum parathyroid hormone (PTH) level in eucalcemic patients after parathyroidectomy for primary hyperparathyroidism has been described in up to 40% of patients, but little is known about its etiology or clinical significance. To better understand the cause of this phenomenon, we studied 49 patients without renal dysfunction or osteomalacia who underwent parathyroidectomy for primary hyperparathyroidism. Patients were categorized into 2 groups based on their serum PTH and calcium levels after parathyroidectomy: (1) elevated PTH with eucalcemia (n = 21), (2) normal PTH with eucalcemia (n = 28). Elevation of serum PTH with eucalcemia after parathyroidectomy occurred in 43% of patients. Patients in group 1 had significantly higher preoperative and postoperative mean serum PTH levels and significantly lower postoperative serum levels of 1,25(OH)(2)D(3), 1,25(OH)(2)D(3)/25(OH)D(3) ratio, and 1,25(OH)(2)D(3)/PTH ratio compared with patients in group 2. Serum PTH in group 1 patients normalized as early as 3 months, but remained elevated in some patients for more than 4 years, and was not associated with development of recurrent hypercalcemia. Normalization of serum PTH in group 1 patients was associated with significant increase in 1,25(OH)(2)D(3) and 1,25(OH)(2)D(3)/PTH ratio. Our data suggest that elevation of serum PTH in eucalcemic patients after parathyroidectomy is a frequently reversible state of resistance of the kidneys to PTH-mediated 1-alpha hydroxylation of 25(OH)D(3) and does not signify subsequent recurrence of hyperparathyroidism.     

Stimulation of 1,25-dihydroxyvitamin D production by parathyroid hormone and hypocalcemia in man

The serum levels of 1.25-dihydroxycholecalciferol [1,25(OH)2D3] were increased in five patients with primary hyperparathyroidism [60 +/- 13 (SD) pg/ml; normal value, 33 +/- 15 (SD) pg/ml] but fell rapidly after parathyroidectomy to values of 23 +/- 9 (SD) pg/ml. This was accompanied by parallel decreases in the serum concentrations of calcium and immunoreactive parathyroid hormone. Over the following 5--35 days, the serum 1,25(OH)2D3 concentrations increased markedly to levels of 59 +/- 17 (SD) pg/ml, which could most likely be explained by a stimulatory effect of the hypocalcemia per se on the renal production of 1,25(OH)2D3.     

Biological activity of FGF-23 and pathophysiologic role in chronic kidney disease

Recent studies indicate that FGF-23, which was originally identified as an endogenous causative factor for hypophosphatemic diseases, is a physiologic factor for the regulation of phosphate homeostasis and vitamin D metabolism. In patients with renal failure, serum concentrations of FGF-23 positively correlate with serum levels of phosphate, Ca-P product, and prathyroid hormone. It is plausible that increased FGF-23 levels are responsible for the reduction of 1,25(OH)2D levels in the early stage of renal insufficiency and also involved in the development of secondary hyperparathyroidism in chronic and end-stage kidney disease.     

Peripheral blood monocyte vitamin D receptor levels are elevated in patients with idiopathic hypercalciuria

Idiopathic hypercalciuria (IH) is the most common cause of calcium oxalate nephrolithiasis. Increased intestinal calcium absorption and bone resorption and decreased tubule calcium reabsorption may be caused by elevated serum 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] in some patients but not in those with normal serum 1,25(OH)(2)D(3) levels. Because 1,25(OH)(2)D(3) exerts its biological actions through binding to the cellular vitamin D receptor (VDR), the present study was undertaken to test the hypothesis that VDR levels are elevated in IH patients.Ten male IH calcium oxalate stone-formers were paired with controls matched in age within 5 yr and lacking a history of stones or family history of stones. Blood was obtained for serum, peripheral blood monocytes (PBMs) were separated from lymphocytes and other mononuclear cells, and PBM VDR content was measured by Western blotting.The PBM VDR level was 2-fold greater in IH men at 49 +/- 21 vs. 20 +/- 15 fmol/mg protein, mean +/- sd; P < 0.008. Serum 1,25(OH)(2)D(3) levels were not higher than controls (48 +/- 14 vs. 39 +/- 11 pg/ml; P < 0.068). In conclusion, PBM VDR levels are elevated in IH calcium oxalate stone-formers. The elevation could not be ascribed to increased serum 1,25(OH)(2)D(3) levels. These results suggest that the molecular basis for IH involves a pathological elevation of tissue VDR level, which may elevate intestinal calcium absorption and bone resorption and decrease renal tubule calcium reabsorption. The mechanism for increased VDR in IH patients with normal serum 1,25(OH)(2)D(3) levels is unknown.     

Hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure

It has been postulated that hyperparathyroidism in chronic renal failure results from hypocalcemia, occurring, in part, from phosphate retention and/or deficient 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] synthesis. However, many studies have failed to demonstrate hyperphosphatemia or low 1,25-(OH)2D levels in patients with mild renal failure. We measured creatinine clearance (CCr), fractional excretion of phosphorus (FEP), and serum phosphorus, ionized calcium, and plasma N-terminal PTH, and 1,25-(OH)2D concentrations in 21 normal subjects and 51 patients with renal failure. Patients with mild renal failure (Ccr, greater than 40 mL/min.1.73 m2) had normal mean serum phosphorus and ionized calcium and decreased mean 1,25-(OH)2D levels compared with those in normal subjects. In patients with moderate renal failure (CCr, 20-40), the mean ionized calcium level was normal, plasma PTH levels and FEP were elevated, and the decrement in 1,25-(OH)2D was more pronounced. The mean ionized calcium level was decreased only in the group of patients with severe renal failure (CCr, less than 20). The 1,25-(OH)2D values correlated positively with CCr and negatively with the log of plasma PTH and serum phosphorus concentrations. Log of plasma PTH correlated negatively with CCr and positively with FEP. The ionized calcium concentration correlated very weakly with CCr and the log of the plasma PTH level. These data demonstrate the presence of hyperparathyroidism, normocalcemia, and 1,25-(OH)2D deficiency in renal failure and are consistent with a role for 1,25-(OH)2D in the suppression of parathyroid activity through as yet unidentified mechanisms.     

A consideration of the hormonal basis and phosphate leak hypothesis of absorptive hypercalciuria

Fifty patients with absorptive hypercalciuria (AH), 25 normal subjects (NS), and 25 nonhypercalciuric patients with stone disease (NHSF) were studied using an oral calcium tolerance test and 24-h urine collections on both a restricted and an unrestricted calcium intake. Mean (+/- SD) fasting fractional calcium excretion was increased in the patients with AH (2.7 +/- 1.1% vs. 1.4 +/- 0.6% in the NS; P less than 0.001) and was negatively correlated with fasting nephrogenous cAMP, suggesting that this renal calcium leak was secondary to parathyroid suppression. Plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] was elevated in 80% of patients with AH and was high normal in the remaining 20%. Ten patients, selected on the basis of results for 1,25-(OH)2D greater than 4 SD from the normal mean, displayed a particularly severe pattern of abnormalities, including mild hypercalcemia in two patients. Pooled data from the NS and patients with AH revealed a significant negative correlation between the plasma concentration of 1,25-(OH)2D and the renal phosphate threshold (r = -0.40; P less than 0.001), but this correlation lost significance when the NHSF were substituted for the NS as a control group (r = -0.07; P = NS). These findings 1) provide a pathophysiological basis for the increase in fasting calcium excretion commonly observed in hypercalciuric patients, and 2) stress the importance of circulating 1,25-(OH)2D in the pathogenesis of the syndrome, but 3) fail to support the phosphate leak theory of pathogenesis.     

Diurnal rhythm of plasma 1,25-dihydroxyvitamin D and vitamin D-binding protein in postmenopausal women: relationship to plasma parathyroid hormone and calcium and phosphate metabolism

OBJECTIVE: Diurnal variations in plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) have previously only been investigated in young individuals, and these studies have failed to demonstrate a diurnal rhythm. We have studied whether plasma levels of 1,25(OH)(2)D and vitamin D-binding protein (DBP) vary in a diurnal rhythm in postmenopausal women. METHODS: Blood and urine were sampled with 2- and 4-h intervals in order to assess diurnal variations in plasma levels of 1,25(OH)(2)D, DBP and parathyroid hormone (PTH), as well as in plasma levels and urinary excretion rates of calcium and phosphate. Additionally, the free 1,25(OH)(2)D index was calculated (the molar ratio of 1,25(OH)(2)D to DBP). RESULTS: Plasma 1,25(OH)(2)D exhibited a diurnal rhythm (P<0.01) with a nadir in the morning (99+/-12 pmol/l), followed by a rapid increase to a plateau during the day (113+/-13 pmol/l, i.e. 14% above nadir level; P=0.005). A similar pattern of variation was found in plasma levels of DBP with peak levels 15% above nadir levels (P<0.01). The free 1,25(OH)(2)D index did not vary in a diurnal rhythm. PTH and plasma levels and urinary excretions of calcium and phosphate exhibited a diurnal pattern of variation. The diurnal rhythm of DBP was correlated with the rhythm of 1,25(OH)(2)D (r=0.47, P<0.01) and plasma albumin (r=0.76, P<0.01). Moreover, the rhythm of plasma calcium and PTH varied inversely (r=-0.36, P=0.02). CONCLUSIONS: With the disclosure of a diurnal rhythm of total plasma 1,25(OH)(2)D, all major hormones and minerals related to calcium homeostasis have now been shown to exhibit diurnal variations. In clinical studies, the diurnal variations of 1,25(OH)(2)D and DBP must be considered, i.e. blood sampling must be standardised according to the time of day.     

Effects of parathyroid hormone and 1,25-dihydroxyvitamin D3 on tubular handling of phosphate in hypophosphatemic rickets

A controlled metabolic study to examine the effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment on the renal handling of phosphate was conducted in nine patients with X-linked dominant hypophosphatemic rickets, including one with autonomous secondary hyperparathyroidism. Administration of 1,25(OH)2D3 resulted in uniform reduction in serum PTH from 63.6 +/- 14.7 (SD) to 49.3 +/- 14.8 muleq/ml (P less than 0.01), elevation of the tubular threshold for phosphate (TmP/GFR) from 1.41 +/- 0.30 to 1.90 +/- 0.31 mg/dl (P less than 0.01) and increase in serum phosphate from 2.6 +/- 0.7 to 3.4 +/- 1.1 mg/dl (P less than 0.01) in eight PTH-suppressible patients. Four patients treated with phosphate before and during the study (group A) excreted significantly more phosphate than those not treated with phosphate (group B) (P less than 0.001). In the control period, group A also had depressed TmP/GFR and higher concentrations of serum phosphate and PTH. With 1,25(OH)2D3 treatment, serum phosphate in group A became remarkably higher than in group B, 4.28 +/- 0.99 vs. 2.55 +/- 0.31 mg/dl (P less than 0.02), whereas serum PTH and TmP/GFR were similar in both groups. A good inverse linear correlation was found between mean serum PTH and mean TmP/GFR of the groups before and after treatment (r = 0.947); whereas, no correlation was found between TmP/GFR and serum calcium. The patient with autonomous secondary hyperparathyroidism, who was also treated with phosphate, had the lowest TmP/GFR. Administration of 1,25(OH)2D3 had no effect on the serum PTH and phosphate concentrations or on TmP/GFR. We conclude that in patients with X-linked dominant hypophosphatemic rickets PTH modulates to some extent the tubular handling of phosphate, and that the importance of this mechanism increases with therapeutic phosphate supplementation. Simultaneous administration of 1,25(OH)2D3 suppressed PTH activity, raised serum phosphate concentrations, and elevated TmP/GFR.     

The role of insulin-like growth factor I in age-related changes in calcium homeostasis in men

The aim of this study was to evaluate hormonal influences on age-related changes in calcium homeostasis in men. We recruited 178 healthy men, ages 20-79 (about 30 per decade). We measured serum calcium, phosphate, urinary calcium, and creatinine clearance. Dietary calcium intake and use of fish oils were determined by questionnaire. Fractional calcium absorption was estimated using the stable strontium technique in a subgroup of 60 men. PTH, 1, 25-dihydroxyvitamin D [1,25(OH)(2)D], 25-hydroxyvitamin D (25OHD), serum insulin-like growth factor I (IGF-I), and testosterone were measured in all men. There was no change in serum calcium with age. There were decreases in serum phosphate, urinary calcium, and creatinine clearance with age (P: < 0.02). Dietary calcium was unchanged. Strontium absorption decreased (P: < 0.01), and PTH increased (P: < 0.001) with age. The data for 1,25OH(2)D were biphasic, reaching a peak at age 55 yr (P: = 0.003). There was a linear increase in 25OHD with age (P: = 0.009) that persisted after correcting for seasonal variation and was positively associated with fish oil use, therefore, the age-related changes in 25OHD were masked by self medication. There were log-linear decreases in IGF-I and testosterone with age (P: < 0.0001). Strontium absorption was not related to 25OHD or 1,25(OH)(2)D, but was positively correlated with IGF-I. 1,25(OH)(2)D correlated negatively with serum phosphate and calcium, but not PTH or creatinine clearance. IGF-I was positively associated with creatinine clearance, serum calcium, and phosphate and negatively associated with PTH (P: < 0.001). In this cross-sectional study of otherwise healthy, normally aging men, age-related decreases in IGF-I seem to have a greater impact on mineral absorption than does vitamin D status.     

Haemodynamic changes following treatment of subclinical and overt hyperthyroidism

OBJECTIVE: A novel assay was employed to study the free 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations in various populations with different levels of 1,25(OH)2D and vitamin D binding protein (DBP). DESIGN: In 12 healthy women before and after 3 months of oral estrogen/progestagen treatment, 10 pregnant women, and 16 patients with a nephrotic syndrome and normal renal function, the concentrations of total and free 1,25(OH)2D, DBP and albumin were assessed. METHODS: The total concentration of 1,25(OH)2D in serum was assessed using a radioreceptor assay. The free fraction of 1,25(OH)2D was measured using symmetric dialysis. DBP was assessed using single radial immunodiffusion. Serum albumin concentrations were measured on an automated analyzer. RESULTS: In healthy women, the concentrations of total 1,25(OH)2D, free 1,25(OH)2D and DBP were 132+/-19 pmol/l, 92+/-30 fmol/l and 5.59+/-0.43 micromol/l. After 3 months of estrogen/progestagen treatment, total 1,25(OH)2D and DBP levels rose significantly to 175+/-51 pmol/l and 8.32+/-1.59 micromol/l (P< or =0.05 and P< or =0.001); the free 1,25(OH)2D remained unchanged (105+/-39 fmol/l; not significant). Pregnant women had significantly higher levels of total 1,25(OH)2D and DBP (239+/-68 pmol/l and 11.32+/-1.77 micromol/l; both P相似文献   

1,25 dihydroxycholecalciferol effects in chronic dialysis. A double-blind controlled study.

1,25 dihydroxycholecalciferol [1,25(OH)2D3] was studied in a double-blind controlled fashion in patients on chronic dialysis. Serum calcium was unchanged in 16 patients on vitamin D3 (D3) (400 to 1200 IU/day). In 15 patients on 1,25(OH)2D3 (0.5 to 1.5 microgram/day), serum calcium increased from 9.05 +/- .15 to 10.25 +/- .20 mg/dl (p less than 0.001), returning to 9.37 +/- .16 mg/dl (p less than 0.001) in the post control period. Patients on D3 showed no reversible decrease in immunoreactive parathyroid hormone levels, but patients on 1,25(OH)2D3 did, from a control of 1077 +/- 258 to 595 +/- 213 microliter equivalents/ml (p less than 0.01), and returned to 1165 +/- 271 microliter equivalents/ml (p less than 0.005). Nine of 12 patients on D3 who underwent serial iliac-crest biopsies showed histologic deterioration, and six of seven who received 1,25(OH)2D3 were improved or unchanged (p less than 0.025). Bone mineral and calcium decreased in patients on D3 (p less than 0.05) but not in those on 1,25(OH)2D3. Hypercalcemia occurred in five of 15 patients. We conclude that 1,25(OH)2D3 has a calcemic effect in chronic dialysis patients, decreases levels of immunoreactive parathyroid hormone, and is associated with histologic improvement in bone disease. Thus, 1,25(OH)2D3 is a valuable adjunct to the management of renal osteodystrophy but requires monitoring of serum calcium to avoid hypercalcemia.