Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats.
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 Ca(2+) 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 17beta-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 parathyroid gland, parathyroid cells did not undergo hyperplasia. These data demonstrate that an increase in endogenous PTH secretion, induced by antagonism of the parathyroid cell Ca(2+) receptor with a small molecule, leads to a dramatic increase in bone turnover, and they suggest a novel approach to the treatment of osteoporosis.
Gowen
M
M
Department of Bone and Cartilage Biology, SmithKline Beecham Pharmaceuticals Inc., King of Prussia, Pennsylvania, USA.
Stroup
G B
GB
Dodds
R A
RA
James
I E
IE
Votta
B J
BJ
Smith
B R
BR
Bhatnagar
P K
PK
Lago
A M
AM
Callahan
J F
JF
DelMar
E G
EG
Miller
M A
MA
Nemeth
E F
EF
Fox
J
J
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D010280:Parathyroid Glands / Q000187:drug effects; D010281:Parathyroid Hormone / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002135:Calcium-Binding Proteins; D010281:Parathyroid Hormone; D004958:Estradiol