Daily transient decreases in plasma parathyroid hormone levels induced by the calcimimetic NPS R-568 slows the rate of bone loss but does not increase bone mass in ovariectomized rats.
Daily parathyroid hormone (PTH) injections that transiently increase plasma PTH levels within the physiological range increase bone mass in osteopenic, ovariectomized (ovx) rats. This study tested the hypothesis that repeated transient decreases in plasma PTH levels from normal, induced by the daily oral administration of the calcimimetic NPS R-568, would induce an anabolic effect in bone of ovx rats with established osteopenia and/or prevent the rapid bone loss that occurs following ovx. In the reversal study, NPS R-568 was administered orally (10 or 100 micromol/kg) for 30 days to 14-month-old retired breeder rats that were ovx 5 months earlier. NPS R-568 treatment did not increase bone formation rate (BFR) or cancellous bone area (B.Ar) in the proximal tibial metaphysis, or bone mineral density (BMD), at any femoral site. In the prevention study, 3-month-old virgin rats were ovx and given NPS R-568 for the following 28 days. The 10 micromol/kg dose prevented the increase in osteoclast number and 42% of the loss of B.Ar, without affecting the elevated osteoblast populations or BFR. Surprisingly, the 100 micromol/kg dose had fewer protective effects, despite preventing the increase in BFR in both cancellous and cortical bone. Detailed analysis of cancellous bone showed that tendency for a dose-related protection of true cancellous bone occurred, but, while the 10 micromol/kg dose prevented 88% of the loss of calcified cartilage seen in control ovx rats, the 100 micromol/kg dose increased that loss by a further 31%. The mechanism underlying these disparate effects of NPS R-568 on calcified cartilage accumulation in the tibial metaphysis is unclear, but may be related to the different effects that the two doses have on plasma Ca(2+) levels. In conclusion, transient increases in PTH levels above basal, and not simple oscillations in hormone levels below normal, appear necessary for the anabolic properties of endogenous PTH to be manifested in the bones of osteopenic ovx rats.
Miller
M A
MA
NPS Pharmaceuticals, Inc., Salt Lake City, UT, USA.
Fox
J
J
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000517:prevention & control*; D002118:Calcium / Q000819:agonists*; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000097:blood*; D010627:Phenethylamines; D011437:Propylamines; D051381:Rats; D017207:Rats, Sprague-Dawley
D000814:Aniline Compounds; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D015675:Osteocalcin; D002118:Calcium