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.
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. 1alpha,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-1alpha-hydroxylase (1alpha-OHase)], a novel vitamin D deficiency model with SHPT.


METHODS
1alpha-OHase-deficient (-/-) mice and normal (+/-) heterozygous littermates re ceived 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 1alpha-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 hy percalcemia was observed at any dose of 1,24(OH)2D2 in normal or 1alpha-OHase-deficient animals. In contrast, 1,25(OH)2D3 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 1alpha-OHase-deficient and normal mice. Treatment with 500 pg/g/day of 1,25(OH)2D3 also induced osteomalacia in normal animals.


CONCLUSIONS
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 1alpha-OHase-deficient mice with SHPT.
Genetics Unit, Shriners Hospital for Children, Montreal, Quebec, Canada. rst-arnaud@shriners.mcgill.ca
R
R
St-Arnaud
A
A
Arabian
V W C
VW
Yu
O
O
Akhouayri
J C
JC
Knutson
S A
SA
Strugnell
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects*; D002114:Calcinosis / Q000139:chemically induced; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004872:Ergocalciferols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005269:Femur / Q000187:drug effects / Q000473:pathology; D006934:Hypercalcemia / Q000235:genetics / Q000517:prevention & control*; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010281:Parathyroid Hormone / Q000097:blood*; D014808:Vitamin D Deficiency / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
D004872:Ergocalciferols; D010281:Parathyroid Hormone; C063087:1,24-dihydroxyvitamin D2; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase