Daily intermittent decreases in serum levels of parathyroid hormone have an anabolic-like action on the bones of uremic rats with low-turnover bone and osteomalacia.
The calcium receptor agonist (calcimimetic) compound NPS R-568 causes rapid decreases in circulating levels of parathyroid hormone (PTH) in rats and humans. We hypothesized that daily intermittent decreases in serum PTH levels may have different effects on bone than do chronically sustained decreases. To test this hypothesis, we compared two NPS R-568 dosing regimens in rats with chronic renal insufficiency induced by two intravenous injections of adriamycin. Fourteen weeks after the second adriamycin injection, creatinine clearance was reduced by 52%, PTH levels were elevated approximately 2.5-fold, and serum 25(OH)D3 and 1,25(OH)2D3 levels were reduced substantially. Treatment by daily per os gavage, which decreased PTH levels intermittently, or continuous subcutaneous infusion, which resulted in a sustained suppression of serum PTH levels, then began for 8 weeks. Despite the hyperparathyroidism, the adriamycin-injected rats developed a low-turnover bone lesion with osteomalacia (fourfold increase in osteoid volume in the proximal tibial metaphysis) and osteopenia (67% decrease in cancellous bone volume and an 18% reduction in bone mineral density at the distal femur). Daily administered (but not infused) NPS R-568 significantly increased cancellous bone volume solely by normalizing trabecular thickness, and increased femoral bone mineral density by 14%. These results indicate that daily intermittent, but not sustained, decreases in PTH levels have an "anabolic-like" effect on bones with a low-turnover lesion in this animal model of chronic renal insufficiency.
Ishii
H
H
Pharmaceutical Development Laboratory, Kirin Brewery Co., Ltd., Takasaki-Shi, Gunma, Japan.
Wada
M
M
Furuya
Y
Y
Nagano
N
N
Nemeth
E F
EF
Fox
J
J
D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000819:agonists / Q000097:blood; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D010018:Osteomalacia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D010281:Parathyroid Hormone / Q000097:blood*; D010627:Phenethylamines; D010710:Phosphates / Q000097:blood; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley; D014511:Uremia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*
D000814:Aniline Compounds; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D010710:Phosphates; D011437:Propylamines; D004317:Doxorubicin; D002118:Calcium