Different vitamin D substrate–product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls

in European Journal of Endocrinology

Context

In healthy subjects and in patients with primary hyperparathyroidism (PH), the administration of a low dose of 25(OH)D (25 μg/day) increases the serum levels of both 25(OH)D and 1,25(OH)2D. It is unknown whether this relationship is present in patients affected by familial benign hypocalciuric hypercalcemia (FBH).

Objective

To evaluate the different vitamin D substrate–product relationship after oral vitamin D supplementation in familial benign hypercalcemia, PH, and healthy controls.

Design

We evaluated the main physiological regulators of 1α-hydroxylase and the substrate–product relationship of 25(OH)D and 1,25(OH)2D in 20 patients with PH, 25 with FBH, and 122 healthy sex- and age-matched controls before and after administration of 25(OH)D for 2 weeks.

Results

25(OH)D increased significantly in all subjects, whereas 1,25(OH)2D serum levels increased significantly in PH patients and healthy controls but not in patients with FBH. Therefore, a significant positive substrate–product relationship of 25(OH)D–1,25(OH)2D was found in PH and healthy controls, but not in FBH. Monomeric calcitonin (hCT-M) was significantly lower at baseline and after 25(OH)D supplementation in the FBH group compared with the other two groups.

Conclusions

The lack of 1,25(OH)2D increase in FBH may be due to a direct inhibitory effect on 1α-hydroxylase of hypercalcemia per se, increased metabolic clearance of 1,25(OH)2D, or a decreased stimulus of 1α-hydroxylase related to persistently low levels of hCT.

Abstract

Context

In healthy subjects and in patients with primary hyperparathyroidism (PH), the administration of a low dose of 25(OH)D (25 μg/day) increases the serum levels of both 25(OH)D and 1,25(OH)2D. It is unknown whether this relationship is present in patients affected by familial benign hypocalciuric hypercalcemia (FBH).

Objective

To evaluate the different vitamin D substrate–product relationship after oral vitamin D supplementation in familial benign hypercalcemia, PH, and healthy controls.

Design

We evaluated the main physiological regulators of 1α-hydroxylase and the substrate–product relationship of 25(OH)D and 1,25(OH)2D in 20 patients with PH, 25 with FBH, and 122 healthy sex- and age-matched controls before and after administration of 25(OH)D for 2 weeks.

Results

25(OH)D increased significantly in all subjects, whereas 1,25(OH)2D serum levels increased significantly in PH patients and healthy controls but not in patients with FBH. Therefore, a significant positive substrate–product relationship of 25(OH)D–1,25(OH)2D was found in PH and healthy controls, but not in FBH. Monomeric calcitonin (hCT-M) was significantly lower at baseline and after 25(OH)D supplementation in the FBH group compared with the other two groups.

Conclusions

The lack of 1,25(OH)2D increase in FBH may be due to a direct inhibitory effect on 1α-hydroxylase of hypercalcemia per se, increased metabolic clearance of 1,25(OH)2D, or a decreased stimulus of 1α-hydroxylase related to persistently low levels of hCT.

Keywords:

Introduction

The vitamin D metabolism is the result of a complex multifactorial control mechanism, and some evidence of a substrate–product relationship between 25(OH)D and 1,25(OH)2D (1, 2, 3) exists. Chronic administration of 1,25(OH)2D increases the metabolic clearance rate of 25(OH)D (4, 5) or decreases its production (6) with consequent depletion of stored 25(OH)D. On the other hand, the administration of elevated doses of vitamin D or 25(OH)D increases the metabolic clearance rate of 1,25(OH)2D (7). This might explain the failure to observe elevations in 1,25(OH)2D after high doses of 25(OH)D (5, 6, 7).

In healthy subjects, the administration of 25(OH)D at a low dose (25 μg) produces an increase in 25(OH)D serum levels within the normal range (below 120 ng/ml) and an increase in 1,25(OH)2D (2, 8). Similarly, exogenous administration of 25(OH)D in patients affected by primary hyperparathyroidism (PH) is followed by an increase in serum levels of 1,25(OH)2D, suggesting a substrate–product relationship in these subjects (9). By contrast, monitoring of 1,25(OH)2D serum levels after administration of 25(OH)D in patients affected by familial benign hypocalciuric hypercalcemia (FBH) has never been performed.

FBH is a rare, benign cause of hypercalcemia, characterized by autosomal-dominant inheritance with high penetrance (10, 11). Affected heterozygous patients typically present with the incidental discovery of hypercalcemia, hypocalciuria, inappropriately normal or only slightly elevated PTH, and, in some subjects, mild-to-moderate hypermagnesemia (10, 11, 12, 13). Moreover, decreased serum levels of monomeric calcitonin (hCT) in basal conditions and after oral calcium stimulation have been found in these patients (14). FBH is typically caused by inactivating mutations of the calcium-sensing receptor (CASR) gene, resulting in inappropriate secretion of PTH and in a markedly enhanced resorption of urinary calcium through mechanisms that are both dependent on and independent of PTH (10, 11, 12, 13, 15, 16, 17, 18, 19, 20). Multiple comparisons between serum concentrations of 1,25(OH)2D in FBH and PH patients at basal conditions have been performed (20, 21, 22, 23, 24). The results showed similar (21, 22) or significantly lower serum levels of 1,25(OH)2D in FBH patients compared with PH patients (20, 23, 24).

The aim of this study was to evaluate the substrate–product relationship of 25(OH)D and 1,25(OH)2D in PH patients, FBH patients, and healthy subjects after oral administration of 25(OH)D.

Materials and methods

Population

Nineteen patients with PH and 25 with FBH were recruited among those attending our clinic. Patients with PH were examined before undergoing surgery, which resulted in a histopathological diagnosis of parathyroid adenoma in 17 patients and parathyroid hyperplasia in two patients. FBH was diagnosed based on the presence of hypercalcemia, normal intact PTH, urinary calcium excretion <200 mg/day (5 mmol/day), and a Ca/Cr clearance ratio <0.01. Among the 25 patients with FBH, eight had a heterozygous missense mutation in exon 6 that substitutes a glutamic acid for glycine at codon 557 (Gly557Glu) (16), two had a P55L mutation (17), 14 had an R648X mutation (18), and one had a Y218C mutation (19). None of the FBH and PH patients had any degree of kinship. In addition to the two patient groups, we recruited 122 healthy controls. The inclusion criteria were age <75 years and normal renal function as evaluated by creatinine clearance measured with MDRD formula (25). The exclusion criteria were concomitant supplementation with calcium and/or vitamin D, renal insufficiency, liver diseases, malabsorption, hypercalciuria, Paget's disease, diabetes mellitus, and any medical treatment that could affect calcium metabolism. Demographical characteristics of patients and controls are resumed in Table 1.

Table 1

Clinical and biochemical data of PH, FBH, and control subjects before and after 25(OH)D treatment (25 μg/day for 2 weeks). Data are presented as mean±s.d.

PHFBHControls
Number of patients1925122
Age (years)60.4±8.358.5±10.361.5±12.4
Sex (F/M)14/616/258/52
BMI (kg/m2)22.6±1.723.4±1.923.9±1.6
Smoking0111
MDRD (ml/min; before treatment)75.1±10.280±7.378±9.1
MDRD (ml/min; after treatment)73.4±8.181.2±9.376.4±7.8
25(OH)D (nmol/l; before treatment)32.32±12.4860.1±24.7156.78±27.73
25(OH)D (nmol/l; after treatment)78.49±39.36*115.72±42.18*114.37±38.36*
1,25(OH)D (pmol/l; before treatment)178.75±27.87†,§76.33±22.36121.47±39.45
1,25(OH)D (pmol/l; after treatment)254.15±53.09*,†,§74.26±39.78172.1±42.12*
Delta 25(OH)D (nmol/l)46.18±13.2355.61±16.9757.71±18.22
Delta 1,25(OH)D (pmol/l)75.4±15.34*,†−2.08±14.04*,‡,§50.08±16.38
hCT (ng/l; before treatment)7.9±0.4§3.7±0.28.1±0.3
hCT (ng/l; after treatment)8.5±0.6§3.6±0.38.2±0.4
PTH (ng/l; before treatment)142.08±13.1†,§44.33±12.838.1±5
PTH (ng/l; after treatment)141.07±10.1†,§43.6±12.840.21±6.5
Ca++ (mmol/l; before treatment)1.37±0.1†,§1.244±0.11.14±0.1
Ca++ (mmol/l; after treatment)1.37±0.1†,§1.248±0.11.14±0.1
Mg++ (mmol/l; before treatment) 0.86±0.080.97±0.040.83±0.3
Mg++ (mmol/l; after treatment) 0.88±0.040.96±0.040.85±0.2
Phosphate (mmol/l; before treatment)0.67±0.021.09±0.061.16±0.03
Phosphate (mmol/l; after treatment)0.71±0.021.09±0.031.16±0.06
Urinary Ca (mg/24 h; before treatment)289±86†,§66.43±28.698.6±35.2
Urinary Ca (mg/24 h; after treatment)298±8†,§66.36±32.5160.5±25.2
*P<0.0083 Student's t-test before and after, P<0.0083 PH vs controls, P<0.0083 FBH vs controls, §P<0.0083 PH vs FBH.

All study participants signed informed consent forms and the Institutional Review Board approved the study, which was conducted in accordance with the Declaration of Helsinki guidelines. All healthy controls and FBH and PH patients were evaluated at baseline and after 2 weeks of oral administration of 25 μg/day of 25(OH)D (Didrogyl, Bruno Farmaceutici, Milan, Italy) while on an unrestricted calcium diet.

Analytical methods

Blood and urinary calcium, phosphate, and creatinine were measured with the Technicon Autoanalyzer SMA-12/60 (Technicon Instruments Corp., Torrytown, NY, USA). Plasma ionized calcium was measured by StatProfile M Nova (Milan, Italy); serum immunoreactive 1–84 PTH was measured using a Nichols kit (Nichols Institute, San Juan Capistrano, CA, USA). Monomeric calcitonin was assessed as previously described (26). Vitamin D metabolites were assessed with the IDS γ-B 25-hydroxy Vitamin D kit (Immunodiagnostic Systems Ltd, Boldon, UK; intra-assay coefficient of variation (CV) 6.9%, interassay CV 9%, normal range 75–300 nmol/l) and IDSγ-B 1,25-dihydroxy Vitamin D kit (Immunodiagnostic Systems Ltd; intra assay CV 9.7%, interassay CV 12%, normal range 39–169 pmol/l). According to the manufacturer, 25(OH)D has a cross-reactivity with 1,25(OH)2D lower than 0.001%.

Statistical analyses

Statistical analyses were performed using the GraphPad 4 package, version 4.0 (GraphPad Software, Inc., San Diego, CA, USA). Differences between single-variable measurements in each group were evaluated with Wilcoxon's signed-rank test. Differences between single variables in different groups were evaluated with the Mann–Whitney U test. A type I error level of 0.05 was chosen. The Bonferroni correction for multiple comparisons was applied considering five variables, which resulted in a new α-error level of 0.0083. Relationships between vitamin D metabolites before and after treatment were analyzed with linear regression using Pearson's correlation coefficients. Regression lines were compared using confidence intervals. A P value lower than 0.05 was considered statistically significant.

Results

At baseline, the serum levels of 25(OH)D in the FBH, PH, and control groups were moderately low, with PH patients showing significantly lower levels than healthy controls (Table 1). After supplementation, the levels increased significantly in all groups, and no meaningful differences were measured among groups.

Serum levels of 1,25(OH)2D at baseline were significantly higher in PH subjects than in healthy controls and in patients with FBH (Table 1). After 2 weeks of 25(OH)D supplementation, the serum 1,25(OH)2D level increased significantly in PH patients and healthy controls. By contrast, no increase in 1,25(OH)2D levels was observed in FBH patients (Table 1). Serum 1,25(OH)2D levels were, therefore, significantly different between the three groups.

As expected, PTH serum levels were significantly higher in the PH group than in the FBH and healthy control groups at baseline and after supplementation. However, no meaningful variations were observed in each group before and after treatment.

At baseline and after 25(OH)D supplementation, hCT was significantly lower in FBH patients compared with the other groups (Table 1).

Ionized calcium levels were significantly different between FBH patients and controls and between PH patients and controls at baseline and after 25(OH)D supplementation, whereas the FBH and PH groups' ionized calcium levels did not differ at any time. Moreover, ionized calcium levels did not change significantly before and after supplementation in each group.

The 24 h urinary calcium levels were significantly different between the three groups, even if the changes after 25(OH)D supplementation were not meaningful.

A significant positive substrate–product relationship of 25(OH)D–1,25(OH)2D was found in PH and control subjects both at baseline and after supplementation, as shown in Fig. 1. No meaningful substrate–product relationship was found in FBH patients before or after 25(OH)D supplementation (Fig. 1). When we analyzed the delta changes of 25(OH)D versus the corresponding delta changes of 1,25(OH)2D in FBH, PH, and controls (Fig. 2), the slope of the 25(OH)D–1,25(OH)2D relationship was higher in PH patients than in controls, whereas no correlation at all was found in the FBH patients. Moreover, no correlation between ionized calcium and either 25(OH)D or 1,25(OH)2D was found in the three groups (data not shown).

Figure 1
Figure 1

Substrate–product relationship for 25(OH)D and 1,25(OH)2D before and after 2-week administration of 25(OH)D.

Citation: European Journal of Endocrinology 164, 5; 10.1530/EJE-10-1053

Figure 2
Figure 2

Relationship between changes in 25(OH)D and corresponding changes in 1,25(OH)2D after two-week administration of 25 μg/day of 25(OH)D in FBH, PH, and healthy controls.

Citation: European Journal of Endocrinology 164, 5; 10.1530/EJE-10-1053

Discussion

Our data support the hypothesis of a substrate–product relationship of 25(OH)D–1,25(OH)2D in PH patients and healthy subjects after oral administration of 25(OH)D. Conversely, in FBH patients, this relationship seems to be lacking. There have been no previous studies investigating the vitamin D substrate–product relationship after vitamin D supplementation in FBH and PH patients.

Our data at baseline confirmed the findings of Law et al. (24) of a lower serum concentration of 1,25(OH)2D in FBH patients compared with PH patients. Interestingly, this difference was still present after 2 weeks of 25(OH)D supplementation. The lack of an increase in 1,25(OH)2D after supplementation could be related to reduced 1α-hydroxylase activity or enhanced metabolic clearance of 1,25(OH)2D, or both.

The activity of renal 1α-hydroxylase is under complex regulation by 25(OH)D, PTH, calcitonin (27), calcium, phosphate, magnesium (28, 29, 30, 31), and 1,25(OH)2D itself (32). 1α-Hydroxylase has been cloned (33, 34, 35), and studies of the molecular mechanisms involved in its regulation demonstrated that administration of PTH and calcitonin, restriction of dietary calcium, and vitamin D deficiency are able to increase 1α-hydroxylase mRNA expression. On the other hand, administration of 1,25(OH)2D results in a decrease in 1α-hydroxylase expression and prevents the increased expression induced by PTH and calcitonin (36). In our study, the increased 1α-hydroxylase activity in PH patients could be related to elevated PTH serum levels, as described previously (24). Low levels of serum phosphate have also been implicated in increased 1α-hydroxylase activity (37). However, in our study, the serum phosphate levels in PH patients were in the low normal range (Table 1).

Recently, it has been discovered that fibroblast growth factor-23 (FGF-23) regulates phosphate and vitamin D homeostasis (38). Phosphate intake and administration of 1,25(OH)2D increase circulating FGF-23 levels, whereas FGF-23 suppress circulating 1,25(OH)2D, to maintain phosphate and vitamin D homeostasis (39). Berndt et al. (38) have postulated that the main regulator of FGF-23 is phosphate; however, it has been recently demonstrated that serum calcium and PTH are also involved in FGF-23 metabolism (39, 40). Considering these findings, FGF-23 might have a role in regulating vitamin D metabolism in FBH patients, probably related to the high serum calcium levels found in these patients. In fact, in our study, phosphorus and 1,25(OH)2D remained in the normality range at both baseline and after 25(OH)D supplementation.

When extra dosage of 25(OH)D is given to healthy subjects, the increase in 1,25(OH)2D and consequent rise in ionized calcium lead to decreased secretion of PTH, which is a regulator of 1α-hydroxylase. In our group of FBH patients, the serum PTH, magnesium, and phosphorus levels were within the normal range, whereas ionized calcium was widely out of range both at baseline and after supplementation. Moreover, after supplementation, even the significant increase in 25(OH)D serum levels did not change the serum 1,25(OH)2D levels. This observation could support the hypothesis that 1α-hydroxylase activity or its induction is impaired in FBH patients, or that hypercalcemia in the presence of normal PTH serum levels in FBH could suppress its activity. It is known that FBH is caused by inactivating mutations of the CASR gene and that CASR in the kidney is localized to the distal and collecting tubules but not the proximal tubules, where 1α-hydroxylase is mainly localized (10, 11, 12, 13). Therefore, hypercalcemia concomitant with normal serum PTH levels may suppress 1α-hydroxylase, regardless of the presence or absence of CASR mutations. Moreover, according to previous works in animal models (41, 42), there is an enhanced metabolic clearance rate of 1,25(OH)2D in the presence of increased serum 24,25(OH)2D concentrations, suggesting that serum 24,25(OH)2D may further enhance 1,25(OH)2D degradation (36). Moreover, Wilhelm et al. (43, 44) demonstrated that 24,25(OH)2D acts as an allosteric effector, diminishing the affinity of 1,25(OH)2D for its receptor and possibly enhancing the clearance rate of 1,25(OH)2D itself. Interestingly, these data were indirectly confirmed in a young patient with vitamin D-resistant rickets in whom the normalization of 24,25(OH)2D serum levels (to the physiological value of 2 ng/ml) brought about a marked and sustained decrease in 1,25(OH)2D serum levels (45). However, because of the high cross-reactivity of the 24,25(OH)2D measurement kit with 25(OH)D, we did not measure 24,25(OH)2D. Finally, it cannot be excluded that the low levels of hCT found in FBH may play a role in the impairment of 1α-hydroxylase (27).

The substrate–product relationship between 25(OH)D and 1,25(OH)2D has been postulated and investigated in previous studies (1, 2, 4). Some authors have reported the lack of a significant substrate–product relationship in experimental models (7). However, in these studies, high doses of 25(OH)D were used, which may have induced an increased clearance rate of 1,25(OH)2D to its final products. In experimental rat models, supplementation with lower doses of 25(OH)D produced an increase in serum 1,25(OH)2D concentrations, demonstrating a close substrate–product relationship between these vitamin D metabolites (46). In humans, Need et al. (1) observed a significant positive relationship between 25(OH)D and 1,25(OH)2D in a large population of postmenopausal women with 25(OH)D levels higher than 40 nmol/l. This positive relationship was subsequently confirmed in postmenopausal women with 25(OH)D levels lower than 40 nmol/l (16.03 mg/dl) (3). This positive substrate–product relationship in humans has also been recently confirmed in other works (2, 8, 47).

Our study has some limitations, the most important of which is the lack of 24,25(OH)2D measurements. However, it should be noted that the commercially available RIA kits for 24,25(OH)2D have a cross-reactivity with 25(OH)D of 100% (48). This prevented us from finding direct proof of an increased 1,25(OH)2D catabolism. Moreover, it is worth mentioning that this has been a short-term study, and lengthy studies are needed to clarify the response of 1,25(OH)2D after 25(OH)D treatment in FBH and PH subjects after a longer period, since it is likely that a new steady state has not yet been established after 2 weeks.

In conclusion, this study has been an interesting opportunity to investigate the vitamin D metabolism and in particular the substrate–product relationship between 25(OH)D and 1,25(OH)2D in patients with FBH, patients with PH, and healthy subjects. The lack of a 1,25(OH)2D increase and a substrate–product relationship in FBH after 25(OH)D supplementation may be due to three possible mechanisms: a direct inhibitory effect on 1α-hydroxylase of hypercalcemia, an increased metabolic clearance of 1,25(OH)2D, and a decreased stimulus of 1α-hydroxylase due to persistently lower levels of hCT in FBH patients compared with patients with PH and healthy subjects.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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    RiscoFTrabaML. Possible involvement of a magnesium dependent mitochondrial alkaline phosphatase in the regulation of the 25-hydroxyvitamin D3-1 alpha-and 25-hydroxyvitamin D3-24R-hydroxylases in LLC-PK1 cells. Magnesium Research19947169178.

    • Search Google Scholar
    • Export Citation
  • 29

    RiscoFTrabaML. Influence of magnesium on the in vitro synthesis of 24,25-dihydroxyvitamin D3 and 1 alpha, 25-dihydroxyvitamin D3. Magnesium Research19925514.

    • Search Google Scholar
    • Export Citation
  • 30

    RiscoFTrabaMLde la PiedraC. Possible alterations of the in vivo 1,25(OH)2 D3 synthesis and its tissue distribution in magnesium-deficient rats. Magnesium Research199582735.

    • Search Google Scholar
    • Export Citation
  • 31

    CarpenterTOCarnesDLJrAnastCS. Effect of magnesium depletion on metabolism of 25-hydroxyvitamin D in rats. American Journal of Physiology1987253E106E113.

    • Search Google Scholar
    • Export Citation
  • 32

    TiosanoDWeismanYHochbergZ. The role of the vitamin D receptor in regulating vitamin D metabolism: a study of vitamin D-dependent rickets, type II. Journal of Clinical Endocrinology and Metabolism20018619081912doi:10.1210/jc.86.5.1908.

    • Search Google Scholar
    • Export Citation
  • 33

    St-ArnaudRMesserlianSMoirJMOmdahlJLGlorieuxFH. The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. Journal of Bone and Mineral Research19971215521559doi:10.1359/jbmr.1997.12.10.1552.

    • Search Google Scholar
    • Export Citation
  • 34

    TakeyamaKKitanakaSSatoTKoboriMYanagisawaJKatoS. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science199727718271830doi:10.1126/science.277.5333.1827.

    • Search Google Scholar
    • Export Citation
  • 35

    FuGKLinDZhangMYBikleDDShackletonCHMillerWLPortaleAA. Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Molecular Endocrinology19971119611970doi:10.1210/me.11.13.1961.

    • Search Google Scholar
    • Export Citation
  • 36

    HewisonMZehnderDBlandRStewartPM. 1alpha-Hydroxylase and the action of vitamin D. Journal of Molecular Endocrinology200025141148doi:10.1677/jme.0.0250141.

    • Search Google Scholar
    • Export Citation
  • 37

    ZhangMYWangXWangJTCompagnoneNAMellonSHOlsonJLTenenhouseHSMillerWLPortaleAA. Dietary phosphorus transcriptionally regulates 25-hydroxyvitamin D-1alpha-hydroxylase gene expression in the proximal renal tubule. Endocrinology2002143587595doi:10.1210/en.143.2.587.

    • Search Google Scholar
    • Export Citation
  • 38

    BerndtTThomasLFCraigTASommerSLiXBergstrahlEJKumarR. Evidence for a signalling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption. PNAS20071041108511090doi:10.1073/pnas.0704446104.

    • Search Google Scholar
    • Export Citation
  • 39

    ImanishiYKobayashiKKawataTTaharaHInabaMNishizawaY. Regulatory mechanisms of circulating fibroblast growth factor 23 in parathyroid diseases. Therapeutic Apheresis and Dialysis200711S32S37doi:10.1111/j.1744-9987.2007.00519.x.

    • Search Google Scholar
    • Export Citation
  • 40

    KobayashiKImanishiYMiyauchiAOnodaNKawataTTaharaHGotoHMikiTakamiHishimuraESugimotoToshitsuguIshikawaraTInabaMNishizawaY. Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism. European Journal of Endocrinology20061549399doi:10.1530/eje.1.02053.

    • Search Google Scholar
    • Export Citation
  • 41

    MatsumotoTIkedaKYamatoHMoritaKEzawaIFukushimaMNishiiYOgataE. Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 metabolism in calcium-deficient rats. Biochemical Journal1988250671677.

    • Search Google Scholar
    • Export Citation
  • 42

    YamatoHMatsumotoTFukumotoSIkedaKIshizukaSOgataE. Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) metabolism in vitamin D-deficient rats infused with 1,25-(OH)2D3. Endocrinology1989124511517doi:10.1210/endo-124-1-511.

    • Search Google Scholar
    • Export Citation
  • 43

    WilhelmFRossFPNormanAW. Specific binding of 24R,25-dihydroxyvitamin D3 to chick intestinal mucosa: 24R,25-dihydroxyvitamin D3 is an allosteric effector of 1,25-dihydroxyvitamin D3 binding. Archives of Biochemistry and Biophysics19862498894doi:10.1016/0003-9861(86)90563-1.

    • Search Google Scholar
    • Export Citation
  • 44

    WilhelmFNormanAW. 24R,25-dihydroxyvitamin D3 regulates 1,25-dihydroxyvitamin D3 binding to its chick intestinal receptor. Biochemical and Biophysical Research Communications1985126496501doi:10.1016/0006-291X(85)90633-3.

    • Search Google Scholar
    • Export Citation
  • 45

    LibermanUASamuelRHalabeAKauliREdelsteinSWeismanYPapapoulosSEClemensTLFraherLJO'RiordanJL. End-organ resistance to 1,25-dihydroxycholecalciferol. Lancet19801504506doi:10.1016/S0140-6736(80)92763-4.

    • Search Google Scholar
    • Export Citation
  • 46

    BreslauNA. Normal and abnormal regulation of 1,25-(OH)2D synthesis. American Journal of the Medical Sciences1988296417425doi:10.1097/00000441-198812000-00009.

    • Search Google Scholar
    • Export Citation
  • 47

    SchoenmakersIGintyFJarjouLMNigdikarSBennettJLaidlawAPrenticeA. Interrelation of parathyroid hormone and vitamin D metabolites in adolescents from the UK and The Gambia. Journal of Steroid Biochemistry and Molecular Biology2010121217220doi:10.1016/j.jsbmb.2010.03.012.

    • Search Google Scholar
    • Export Citation
  • 48

    ParviainenMTSavolainenKEKorhonenPHAlhavaEMVisakorpiJK. An improved method for routine determination of vitamin D and its hydroxylated metabolites in serum from children and adults. Clinica Chimica Acta1981114233247doi:10.1016/0009-8981(81)90396-X.

    • Search Google Scholar
    • Export Citation

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    Substrate–product relationship for 25(OH)D and 1,25(OH)2D before and after 2-week administration of 25(OH)D.

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    Relationship between changes in 25(OH)D and corresponding changes in 1,25(OH)2D after two-week administration of 25 μg/day of 25(OH)D in FBH, PH, and healthy controls.

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    NeedAGHorowitzMMorrisHANordinBC. Vitamin D status: effects on parathyroid hormone and 1,25-dihydroxyvitamin D in postmenopausal women. American Journal of Clinical Nutrition20007115771581.

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    BevilacquaMDominguezLJGandoliniGValdesVVagoTRighiniVBarrellaMBarbagalloM. Vitamin D substrate–product relationship in idiopathic hypercalciuria. Journal of Steroid Biochemistry and Molecular Biology200911338doi:10.1016/j.jsbmb.2008.08.010.

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    RejnmarkLVestergaardPHeickendorffLMosekildeL. Plasma 1,25(OH)2D levels decrease in postmenopausal women with hypovitaminosis D. European Journal of Endocrinology2008158571576doi:10.1530/EJE-07-0844.

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    ClementsMRDaviesMHayesMEHickeyCDLumbGAMawerEBAdamsPH. The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency. Clinical Endocrinology1992371727doi:10.1111/j.1365-2265.1992.tb02278.x.

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    HalloranBPBikleDDLevensMJCastroMEGlobusRKHoltonE. Chronic 1,25-dihydroxyvitamin D3 administration in the rat reduces the serum concentration of 25-hydroxyvitamin D by increasing metabolic clearance rate. Journal of Clinical Investigation198678622628doi:10.1172/JCI112619.

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    ReinholzGGDeLucaHF. Inhibition of 25-hydroxyvitamin D3 production by 1,25-dihydroxyvitamin D3 in rats. Archives of Biochemistry and Biophysics19983557783doi:10.1006/abbi.1998.0706.

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    HendyGND'Souza-LiLYangBCanaffLColeDE. Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Human Mutation200016281296doi:10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A.

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    BevilacquaMDominguezLJRighiniVValdesVVagoTLeopaldiEBaldiGBarrellaMBarbagalloM. Dissimilar PTH, gastrin, and calcitonin responses to oral calcium and peptones in hypocalciuric hypercalcemia, primary hyperparathyroidism, and normal subjects: a useful tool for differential diagnosis. Journal of Bone and Mineral Research200621406412doi:10.1359/JBMR.051210.

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    JapTSWuYCJenqSFWonGS. A novel mutation in the calcium-sensing receptor gene in a Chinese subject with persistent hypercalcemia and hypocalciuria. Journal of Clinical Endocrinology and Metabolism2001861315doi:10.1210/jc.86.1.13.

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    NakayamaTMinatoMNakagawaMSomaMTobeHAoiNKosugeKSatoMOzawaYKanmatsuseKKokubunS. A novel mutation in Ca2+-sensing receptor gene in familial hypocalciuric hypercalcemia. Endocrine200115277282doi:10.1385/ENDO:15:3:277.

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    SpeerGTothMNillerHHSalamonDTakacsIMihellerPPatocsANagyZBajnokENyiriPLakatosP. Calcium metabolism and endocrine functions in a family with familial hypocalciuric hypercalcemia. Experimental and Clinical Endocrinology and Diabetes2003111486490doi:10.1055/s-2003-44708.

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    YamauchiMSugimotoTYamaguchiTYanoSWangJBaiMBrownEMChiharaK. Familial hypocalciuric hypercalcemia caused by an R648stop mutation in the calcium-sensing receptor gene. Journal of Bone and Mineral Research20021721742182doi:10.1359/jbmr.2002.17.12.2174.

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    CetaniFPardiEBorsariSTonaccheraMMorabitoEPincheraAMarcocciCDipollinaG. Two Italian kindreds with familial hypocalciuric hypercalcaemia caused by loss-of-function mutations in the calcium-sensing receptor (CaR) gene: functional characterization of a novel CaR missense mutation. Clinical Endocrinology200358199206doi:10.1046/j.1365-2265.2003.01696.x.

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    ChristensenSENissenPHVestergaardPHeickendorffLRejnmarkLBrixenKMosekildeL. Skeletal consequences of familial hypocalciuric hypercalcaemia versus primary hyperparathyroidism. Clinical Endocrinology200971798807doi:10.1111/j.1365-2265.2009.03557.x.

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    GilbertFD'AmourPGascon-BarreMBoutinJMHavramkovaJBelangerRMatteR. Familial hypocalciuric hypercalcemia: description of a new kindred with emphasis on its difference from primary hyperparathyroidism. Clinical and Investigative Medicine198587884.

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    JacqzEGarabedianMGuillozoHBourdeauAGuillotMGagnadouxMFBroyerMLenoirGBalsanS. Circulating metabolites of vitamin D in 14 children with hypercalcemia. Archives Françaises de Pédiatrie198542225230.

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    DaviesMAdamsPHBerryJLLumbGAKlimiukPSMawerEBWainD. Familial hypocalciuric hypercalcaemia: observations on vitamin D metabolism and parathyroid function. Acta Endocrinologica1983104210215doi:10.1530/acta.0.1040210.

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    LawWMJrBollmanSKumarRHeathHIII. Vitamin D metabolism in familial benign hypercalcemia (hypocalciuric hypercalcemia) differs from that in primary hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism198458744747doi:10.1210/jcem-58-4-744.

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    LeveyASBoschJPLewisJBGreeneTRogersNRothD. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Annals of Internal Medicine1999130461470.

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    BevilacquaMDominguezLJRighiniVValdesVToscanoRSangalettiOVagoTBaldiGBarrellaMBianchi-PorroG. Increased gastrin and calcitonin secretion after oral calcium or peptones administration in patients with hypercalciuria: a clue to an alteration in calcium-sensing receptor activity. Journal of Clinical Endocrinology and Metabolism20059014891494doi:10.1210/jc.2004-0045.

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    ShinkiTUenoYDeLucaHFSudaT. Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D3-1alpha-hydroxylase gene in normocalcemic rats. PNAS19999682538258doi:10.1073/pnas.96.14.8253.

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  • 28

    RiscoFTrabaML. Possible involvement of a magnesium dependent mitochondrial alkaline phosphatase in the regulation of the 25-hydroxyvitamin D3-1 alpha-and 25-hydroxyvitamin D3-24R-hydroxylases in LLC-PK1 cells. Magnesium Research19947169178.

    • Search Google Scholar
    • Export Citation
  • 29

    RiscoFTrabaML. Influence of magnesium on the in vitro synthesis of 24,25-dihydroxyvitamin D3 and 1 alpha, 25-dihydroxyvitamin D3. Magnesium Research19925514.

    • Search Google Scholar
    • Export Citation
  • 30

    RiscoFTrabaMLde la PiedraC. Possible alterations of the in vivo 1,25(OH)2 D3 synthesis and its tissue distribution in magnesium-deficient rats. Magnesium Research199582735.

    • Search Google Scholar
    • Export Citation
  • 31

    CarpenterTOCarnesDLJrAnastCS. Effect of magnesium depletion on metabolism of 25-hydroxyvitamin D in rats. American Journal of Physiology1987253E106E113.

    • Search Google Scholar
    • Export Citation
  • 32

    TiosanoDWeismanYHochbergZ. The role of the vitamin D receptor in regulating vitamin D metabolism: a study of vitamin D-dependent rickets, type II. Journal of Clinical Endocrinology and Metabolism20018619081912doi:10.1210/jc.86.5.1908.

    • Search Google Scholar
    • Export Citation
  • 33

    St-ArnaudRMesserlianSMoirJMOmdahlJLGlorieuxFH. The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. Journal of Bone and Mineral Research19971215521559doi:10.1359/jbmr.1997.12.10.1552.

    • Search Google Scholar
    • Export Citation
  • 34

    TakeyamaKKitanakaSSatoTKoboriMYanagisawaJKatoS. 25-Hydroxyvitamin D3 1alpha-hydroxylase and vitamin D synthesis. Science199727718271830doi:10.1126/science.277.5333.1827.

    • Search Google Scholar
    • Export Citation
  • 35

    FuGKLinDZhangMYBikleDDShackletonCHMillerWLPortaleAA. Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Molecular Endocrinology19971119611970doi:10.1210/me.11.13.1961.

    • Search Google Scholar
    • Export Citation
  • 36

    HewisonMZehnderDBlandRStewartPM. 1alpha-Hydroxylase and the action of vitamin D. Journal of Molecular Endocrinology200025141148doi:10.1677/jme.0.0250141.

    • Search Google Scholar
    • Export Citation
  • 37

    ZhangMYWangXWangJTCompagnoneNAMellonSHOlsonJLTenenhouseHSMillerWLPortaleAA. Dietary phosphorus transcriptionally regulates 25-hydroxyvitamin D-1alpha-hydroxylase gene expression in the proximal renal tubule. Endocrinology2002143587595doi:10.1210/en.143.2.587.

    • Search Google Scholar
    • Export Citation
  • 38

    BerndtTThomasLFCraigTASommerSLiXBergstrahlEJKumarR. Evidence for a signalling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption. PNAS20071041108511090doi:10.1073/pnas.0704446104.

    • Search Google Scholar
    • Export Citation
  • 39

    ImanishiYKobayashiKKawataTTaharaHInabaMNishizawaY. Regulatory mechanisms of circulating fibroblast growth factor 23 in parathyroid diseases. Therapeutic Apheresis and Dialysis200711S32S37doi:10.1111/j.1744-9987.2007.00519.x.

    • Search Google Scholar
    • Export Citation
  • 40

    KobayashiKImanishiYMiyauchiAOnodaNKawataTTaharaHGotoHMikiTakamiHishimuraESugimotoToshitsuguIshikawaraTInabaMNishizawaY. Regulation of plasma fibroblast growth factor 23 by calcium in primary hyperparathyroidism. European Journal of Endocrinology20061549399doi:10.1530/eje.1.02053.

    • Search Google Scholar
    • Export Citation
  • 41

    MatsumotoTIkedaKYamatoHMoritaKEzawaIFukushimaMNishiiYOgataE. Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 metabolism in calcium-deficient rats. Biochemical Journal1988250671677.

    • Search Google Scholar
    • Export Citation
  • 42

    YamatoHMatsumotoTFukumotoSIkedaKIshizukaSOgataE. Effect of 24,25-dihydroxyvitamin D3 on 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) metabolism in vitamin D-deficient rats infused with 1,25-(OH)2D3. Endocrinology1989124511517doi:10.1210/endo-124-1-511.

    • Search Google Scholar
    • Export Citation
  • 43

    WilhelmFRossFPNormanAW. Specific binding of 24R,25-dihydroxyvitamin D3 to chick intestinal mucosa: 24R,25-dihydroxyvitamin D3 is an allosteric effector of 1,25-dihydroxyvitamin D3 binding. Archives of Biochemistry and Biophysics19862498894doi:10.1016/0003-9861(86)90563-1.

    • Search Google Scholar
    • Export Citation
  • 44

    WilhelmFNormanAW. 24R,25-dihydroxyvitamin D3 regulates 1,25-dihydroxyvitamin D3 binding to its chick intestinal receptor. Biochemical and Biophysical Research Communications1985126496501doi:10.1016/0006-291X(85)90633-3.

    • Search Google Scholar
    • Export Citation
  • 45

    LibermanUASamuelRHalabeAKauliREdelsteinSWeismanYPapapoulosSEClemensTLFraherLJO'RiordanJL. End-organ resistance to 1,25-dihydroxycholecalciferol. Lancet19801504506doi:10.1016/S0140-6736(80)92763-4.

    • Search Google Scholar
    • Export Citation
  • 46

    BreslauNA. Normal and abnormal regulation of 1,25-(OH)2D synthesis. American Journal of the Medical Sciences1988296417425doi:10.1097/00000441-198812000-00009.

    • Search Google Scholar
    • Export Citation
  • 47

    SchoenmakersIGintyFJarjouLMNigdikarSBennettJLaidlawAPrenticeA. Interrelation of parathyroid hormone and vitamin D metabolites in adolescents from the UK and The Gambia. Journal of Steroid Biochemistry and Molecular Biology2010121217220doi:10.1016/j.jsbmb.2010.03.012.

    • Search Google Scholar
    • Export Citation
  • 48

    ParviainenMTSavolainenKEKorhonenPHAlhavaEMVisakorpiJK. An improved method for routine determination of vitamin D and its hydroxylated metabolites in serum from children and adults. Clinica Chimica Acta1981114233247doi:10.1016/0009-8981(81)90396-X.

    • Search Google Scholar
    • Export Citation