Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats

被引:214
作者
Gowen, M
Stroup, GB
Dodds, RA
James, IE
Votta, BJ
Smith, BR
Bhatnagar, PK
Lago, AM
Callahan, JF
DelMar, EG
Miller, MA
Nemeth, EF
Fox, J
机构
[1] NPS Pharmaceut Inc, Salt Lake City, UT 84108 USA
[2] SmithKline Beecham Pharmaceut Inc, Dept Bone & Cartilage Biol, King Of Prussia, PA USA
[3] SmithKline Beecham Pharmaceut Inc, Dept Drug Metab, King Of Prussia, PA USA
[4] SmithKline Beecham Pharmaceut Inc, Dept Med Chem, King Of Prussia, PA USA
关键词
D O I
10.1172/JCI9038
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Parathyroid hormone (PTH) is an effective bone anabolic agent, but it must be administered parenterally. An orally active anabolic agent would provide a valuable alternative for treating osteoporosis. NPS 2143 is a novel, selective antagonist (a "calcilytic") of the parathyroid cell Ca2+ receptor. Daily oral administration of NPS 2143 to osteopenic ovariectomized (OVX) rats caused a sustained increase in plasma PTH levels, provoking a dramatic increase in bone turnover but no net change in bone mineral density. Concurrent oral administration of NPS 2143 and subcutaneous infusion of 17 beta-estradiol also resulted in increased bone turnover. However, the antiresorptive action of estrogen decreased the extent of bone resorption stimulated by the elevated PTH levels, leading to an increase in bone mass compared with OVX controls or to either treatment alone. Despite the sustained stimulation to the parathyoid gland, parathyroid cells did not undergo hyperplasia. These data demonstrate that an increase in endogenous PTH secretion, induced by antagonism of the parathyroid cell Ca2+ receptor with a small molecule, leads to a dramatic increase in bone turnover, and they suggest a novel approach to the treatment of osteoporosis.
引用
收藏
页码:1595 / 1604
页数:10
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