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Comparison of Active Vitamin D Compounds and a Calcimimetic in Mineral Homeostasis

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Comparison of Active Vitamin D Compounds and a Calcimimetic in Mineral Homeostasis BASIC RESEARCH www.jasn.org Comparison of Active Vitamin D Compounds and a Calcimimetic in Mineral Homeostasis Loan Nguyen-Yamamoto,* Isabel Bolivar,* Stephen A. Strugnell,† and David Goltzman* *Department of Medicine, McGill University and McGill University Health Centre, Montreal, Quebec, Canada; and †Genzyme Corporation, Middleton, Wisconsin ABSTRACT The differential effects between cinacalcet and active vitamin D compounds on parathyroid function, mineral metabolism, and skeletal function are incompletely understood. Here, we studied cinacalcet and active vitamin D compounds in mice expressing the null mutation for Cyp27b1, which encodes 25- ␣ hydroxyvitamin D-1 -hydroxylase, thereby lacking endogenous 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Vehicle-treated mice given high dietary calcium had hypocalcemia, hypophosphatemia, and marked secondary hyperparathyroidism. Doxercalciferol and 1,25(OH)2D3 each normalized these parameters and corrected both the abnormal growth plate architecture and the diminished longitudinal bone growth observed in these mice. In contrast, cinacalcet suppressed serum parathyroid hormone (PTH) cyclically and did not correct the skeletal abnormalities and hypocalcemia persisted. Vehicle-treated mice given a BASIC RESEARCH “rescue diet” (high calcium and phosphorus, 20% lactose) had normal serum calcium and PTH levels; cinacalcet induced transient hypocalcemia and mild hypercalciuria. The active vitamin D compounds and cinacalcet normalized the increased osteoblast activity observed in mice with secondary hyperparathy- roidism; cinacalcet, however, increased the number and activity of osteoclasts. In conclusion, cinacalcet reduces PTH in a cyclical manner, does not eliminate hypocalcemia, and does not correct abnormalities of the growth plate. Doxercalciferol and 1,25(OH)2D3 reduce PTH in a sustained manner, normalize serum calcium, and improve skeletal abnormalities. J Am Soc Nephrol 21: ●●●–●●●, 2010. doi: 10.1681/ASN.2009050531 2ϩ Vitamin D and extracellular calcium ([Ca ]e) play and/or serum fibroblast growth factor 23 (FGF-23), central roles in regulating systemic calcium ho- and in part because of loss of renal parenchyma. 2ϩ meostasis. [Ca ]e activates a cation-sensing Consequently, low levels of 1,25(OH)2D develop G-protein coupled receptor, the calcium-sensing in stage 3 CKD, leading to reduced calcium ab- receptor (CaSR), to modulate the concentrations of sorption.3 The resultant hypocalcemia and low circulating parathyroid hormone (PTH) and to reg- 1,25(OH)2D can lead to the development of sec- ulate renal calcium re-absorption.1 The activated ondary hyperparathyroidism, mainly because of form of vitamin D, 1,25-dihydroxyvitamin D the fact that extracellular ionized calcium 2ϩ [1,25(OH)2D] is synthesized via the action of the [Ca ]e and 1,25(OH)2D regulate PTH biosyn- enzyme 25-hydroxyvitamin D-1␣-hydroxylase ␣ [1 (OH)ase], which converts 25-hydroxyvitamin Received May 21, 2009. Accepted May 24, 2010. D to 1,25(OH)2D. This activated form of vitamin D Published online ahead of print. Publication date available at acts predominantly on a nuclear vitamin D receptor www.jasn.org. (VDR) to modulate parathyroid function, mineral Correspondence: 2 Dr. David Goltzman, Royal Victoria Hospital, metabolism, and skeletal function. 1,25(OH)2D Room H467, 687 Pine Avenue West, Montreal, Quebec, Canada synthesis is impaired in chronic kidney disease H3A 1A1. Phone: 514-843-1632; Fax: 514-843-1712; E-mail: (CKD), at least in part because of suppression of the [email protected] renal 1␣(OH)ase by elevated serum phosphorus Copyright © 2010 by the American Society of Nephrology J Am Soc Nephrol 21: ●●●–●●●, 2010 ISSN : 1046-6673/2110-●●● 1 BASIC RESEARCH www.jasn.org thesis, with 1,25(OH)2D predominantly suppressing PTH pocalcemic and hypophosphatemic and had markedly increased ϩ 4,5 2 gene transcription and [Ca ]e predominantly downregu- serum PTH (Figure 1), doxercalciferol normalized serum calcium 6,7 8 lating PTH mRNA translation. Both calcium and activated and serum phosphorus. 1,25(OH)2D3 similarly increased serum vitamin D9,10 coordinately regulate the growth of the parathy- calcium (Figure 1A) but increased serum phosphorus more 2ϩ roid gland. In addition, increased [Ca ]e, by activating the markedly than doxercalciferol (Figure 1C). Doxercalciferol 1 CaSR, potently suppresses PTH secretion. The ensuing sec- and 1,25(OH)2D3 each dramatically reduced circulating con- ondary hyperparathyroidism, with disordered skeletal remod- centrations of PTH (Figure 1D). With cinacalcet treatment, eling and mineralization defects, can contribute to the mani- serum calcium remained low at 2 and 24 hours after dose ad- festations of renal osteodystrophy. ministration (Figure 1A), and cyclic PTH fluctuations were Active vitamin D compounds including 1,25(OH)2D3 (calcit- observed (Figure 1D): that is, PTH levels decreased at 2 hours 11 ␣ riol) and doxercalciferol [1 OHD2, Hec- 12 torol], a vitamin D2 analog that undergoes metabolic activation in vivo to form 1,25(OH)2D2, are used clinically to manage elevated PTH in CKD. The calcimimetic ci- nacalcet, an allosteric modulator of the CaSR, requires the presence of calcium ions to be effective13 and is used clinically to man- age secondary hyperparathyroidism.14 Cina- calcet has also been approved for use in pri- mary hyperparathyroidism due to parathyroid carcinoma.15 Recently, calcimi- metics have been proposed as a potential ad- juvant treatment for familial hypophos- phatemic rickets, which is complicated by secondary hyperparathyroidism.16 How- ever, the skeletal impact of calcimimetics is unclear. We therefore compared active vita- min D compounds and the calcimimetic, ci- nacalcet, in mice with targeted inactivation of Cyp27b1, the gene encoding the 1␣(OH)ase enzyme, that lack the capacity to synthesize endogenous 1,25(OH)2D. We Figure 1. Active vitamin D compounds and cinacalcet affect calcium, phosphorus, and exposed these mice [1␣(OH)ase null mice] parathyroid homeostasis differently. Serum and urine biochemistry and histomorphom- to two different environments: a high-cal- etry of the parathyroid glands are shown: in wild-type (WT) mice; in 1␣(OH)ase null mice ␣ Ϫ/Ϫ cium intake on which 1␣(OH)ase null mice [1 (OH)ase ] on a high-calcium intake (h) treated with vehicle, 1,25(OH)2D3, doxercal- ␣ are known to develop secondary hyperpara- ciferol, cinacalcet for 2 hours (hr), and cinacalcet for 24 hours; and in 1 (OH)ase null mice thyroidism, rickets, and osteomalacia17–19 on a rescue diet (r) treated with vehicle or cinacalcet for 24 hours. Each value is the mean Ϯ SEM. (A) Number of replicates for serum calcium from left to right are as follows: and a “rescue” diet18 containing high cal- 4 for WT, 6 for vehicle, 5 for 1,25(OH)2D3,7 for doxercalciferol, 3 for cinacalcet 2 hours, 3 cium, high phosphorus, and 20% lactose, for cinacalcet 24 hours, 7 for vehicle, 5 for cinacalcet 2 hours, and 5 for cinacalcet 24 which is known to normalize serum calcium hours. (B) Number of replicates for 24-hour urine calcium are as follows: 4 for vehicle and and phosphate in the absence of either active 4 for cinacalcet. (C) Number of replicates for serum phosphorus from left to right are as vitamin D or the vitamin D receptor. We follows: 3 for WT, 4 for vehicle, 4 for 1,25(OH)2D3, 6 for doxercalciferol, 3 for cinacalcet then determined the relative effects of active 2 hours, 3 for cinacalcet 24 hours, 6 for vehicle, 4 for cinacalcet 2 hours, and 5 for vitamin D compounds and calcimimetics cinacalcet 24 hours. (D) Number of replicates for serum PTH from left to right are as on parathyoid gland function, mineral ho- follows: 3 for WT, 7 for vehicle, 5 for 1,25(OH)2D3, 7 for doxercalciferol, 3 for cinacalcet meostasis, and skeletal function. 2 hours, 3 for cinacalcet 24 hours, 4 for vehicle, 4 for cinacalcet 2 hours, and 5 for cinacalcet 2 hours. (E) Number of replicates for parathyroid gland size done by histomor- phometry from left to right are as follows: 3 for WT, 3 for vehicle, 3 for 1,25(OH)2D3, 3 for ϩ doxercalciferol, 3 for cinacalcet, 6 for vehicle, and 6 for cinacalcet. P Ͻ 0.05 compared RESULTS ϩϩ ϩϩϩ with WT mice; P Ͻ 0.01 compared with WT mice; P Ͻ 0.001 compared with WT mice; *P Ͻ 0.05 compared with vehicle-treated 1␣(OH)ase null mice on a high-calcium Serum Biochemistry and intake; **P Ͻ 0.01 compared with vehicle-treated 1␣(OH)ase null mice on a high-calcium Parathyroid Gland Histology intake; ***P Ͻ 0.001 compared with vehicle-treated 1␣(OH)ase null mice on a high- E Although vehicle-treated 1␣(OH)ase null calcium intake. P Ͻ 0.05 compared with vehicle-treated 1␣(OH)ase null mice on a rescue EE mice on the high-calcium intake were hy- diet; P Ͻ 0.01 compared with vehicle-treated 1␣(OH)ase null mice on a rescue diet. 2 Journal of the American Society of Nephrology J Am Soc Nephrol 21: ●●●–●●●, 2010 www.jasn.org BASIC RESEARCH after dose administration, but re- bounded by 24 hours, although not to vehicle-treated levels (Figure 1D). 1,25(OH)2D3 and doxercalciferol both decreased the size of the parathyroid glands below that seen in the vehicle- treated 1␣(OH)ase null mice on a high- calcium diet (Figure 1E); parathyroid glands remained enlarged however in the cinacalcet-treated mice (Figure 1, D and E). On the rescue diet, serum calcium, phosphorus, and PTH were normalized in null mice (Figure 1, A, C, and D, re- spectively). Cinacalcet treatment signif- icantly reduced serum calcium after 2 hours [although not to the levels seen in Figure 2. Active vitamin D compounds but not cinacalcet normalize an unmineralized the vehicle-treated 1␣(OH)ase null growth plate and unmineralized bone. Representative von Kossa stains of (A) the growth ␣ mice on the high-calcium intake], but plates and (B) the metaphyses are shown: of the tibiae of wild-type mice; of 1 (OH)ase ␣ Ϫ/Ϫ null mice [1 (OH)ase ] on a high-calcium intake (h) treated with vehicle, 1,25(OH)2D3, not after 24 hours (Figure 1A).
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