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1α,24(S)(OH)2D2 normalizes bone morphology and serum parathyroid hormone without hypercalcemia in 25-hydroxyvitamin D-1-hydroxylase (CYP27B1)-deficient mice, an animal model of vitamin D deficiency with secondary hyperparathyroidism

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Abstract

Background: Vitamin D compounds are effective in managing elevated PTH levels in secondary hyperparathyroidism (SHPT) of renal failure. However, undesired increases in serum calcium and phosphorus associated with compounds such as calcitriol [1,25(OH)2D3] has prompted a search for compounds with improved safety profiles. 1α,24(S)(OH)2D2 (1,24(OH)2D2) is a vitamin D2 metabolite with low calcium-mo bilizing activity in vivo. We studied the efficacy of 1,24(OH)2D2 in mice lacking the CYP27B1 enzyme [25-hydroxyvitamin D-1α-hydroxylase (1α-OHase)], a novel vitamin D deficiency model with SHPT. Materials and methods: 1α-OHase-deficient (−/−) mice and normal (+/−) heterozygous littermates received 1,24(OH)2D2 (100, 300, 1000, and 3000 pg/g/day) or 1,25(OH)2D3 (30, 300, and 500 pg/g/day) for 5 weeks via daily sc injection. Control groups received vehicle. Results: Vehicle-treated 1α-OHase-deficient mice were hypocalcemic and had greatly elevated serum PTH. 1,24(OH)2D2 at doses above 300 pg/g/day normalized serum calcium, serum PTH, bone growth plate morphology, and other bone parameters. No hypercalcemia was observed at any dose of 1,24(OH)2D2 in normal or 1α-OHase-deficient animals. In contrast, 1,25(OH)2D2 at only 30 pg/g/day normalized calcemia, serum PTH, and bone parameters, but at higher doses completely suppressed PTH and caused hypercalcemia in both 1α-OHase-deficient and normal mice. Treatment with 500 pg/g/day of 1,25(OH)2D3 also induced osteomalacia in normal animals. Conclusion: 1,25(OH)2D3 was maximally active at 10-fold lower doses than 1,24(OH)2D2, but induced hypercalcemia and osteomalacia at high doses. 1,24(OH)2D2 normalized serum calcium, serum PTH, and bone histomorphometry without hypercalcemia in 1α-OHase-deficient mice with SHPT.

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Authors and Affiliations

  1. Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montreal, Quebec, Canada, H3G 1A6

    R. St-Arnaud PhD, A. Arabian, V. W. C. Yu & O. Akhouayri

  2. Departments of Medicine, Surgery, and Human Genetics, McGill University, Montreal, Quebec, Canada, H3A 2T5

    R. St-Arnaud PhD

  3. Pharmacology and Preclinical Research, Genzyme Inc., Aspen Commons, Middleton, Wisconsin, USA

    J. C. Knutson & S. A. Strugnell

Authors
  1. R. St-Arnaud PhD
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  2. A. Arabian
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  3. V. W. C. Yu
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  4. O. Akhouayri
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  5. J. C. Knutson
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  6. S. A. Strugnell
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Correspondence to R. St-Arnaud PhD.

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St-Arnaud, R., Arabian, A., Yu, V.W.C. et al. 1α,24(S)(OH)2D2 normalizes bone morphology and serum parathyroid hormone without hypercalcemia in 25-hydroxyvitamin D-1-hydroxylase (CYP27B1)-deficient mice, an animal model of vitamin D deficiency with secondary hyperparathyroidism. J Endocrinol Invest 31, 711–717 (2008). https://doi.org/10.1007/BF03346420

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