Edward F. Nemeth

Calcimimetic Compounds: a Direct Approach to Controlling Plasma Levels of Parathyroid Hormone in Hyperparathyroidism.

The Ca2+ receptor is the primary mechanism regulating the secretion of parathyroid hormone (PTH). Ligands that activate this receptor (calcimimetics) represent a novel means of lowering plasma levels of PTH. Two mechanistically distinct classes of calcimimetics that inhibit PTH secretion have been identified: type I calcimimetics are full agonists of the Ca2+ receptor and include Ca2+ and other polyvalent inorganic and organic cations; whereas type II calcimimetics, typified by phenylalkylamine compounds, behave like positive allosteric activators and increase, in a stereoselective manner, the sensitivity of the Ca2+ receptor to activation by extracellular Ca2+. The phenylalkylamine calcimimetics are orally active and decrease the plasma levels of PTH and Ca2+ in patients with primary hyperparathyroidism (HPT), a disease that so far has resisted pharmacological intervention. Such compounds are similarly safe and effective in reducing PTH levels and preventing parathyroid cell hyperplasia in rats with HPT secondary to chronic renal insufficiency and they lower plasma levels of PTH in dialysis patients with secondary HPT. Calcimimetic compounds may provide a novel therapy for treating both primary and secondary HPT.

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.

The calcimimetic NPS R-568 decreases plasma PTH in rats with mild and severe renal or dietary secondary hyperparathyroidism.

NPS R-568 is a Ca2+ receptor agonist (“calcimimetic”) compound that reduces circulating parathyroid hormone (PTH) levels in rats and humans with mild secondary hyperparathyroidism (2°HPT) resulting from chronic renal insufficiency (CRI). These studies extend those observations to show that NPS R-568 is equally effective in decreasing plasma PTH and Ca2+ levels in rats with mild or severe 2°HPT, resulting either from CRI or from dietary calcium deficiency. Male rats were 5/6 nephrectomized and fed either normal chow or a high-phosphorus diet; other normal rats were fed a low-calcium diet. When 2°HPT had developed, NPS R-568 was administered and blood samples were collected for up to 6 h. PTH levels decreased to a minimum level within 30 min in both CRI and calcium deficiency models of 2°HPT. PTH and Ca2+ levels remained significantly depressed for >3 h after dosing. The percentage decrease in PTH levels was unaffected by the severity of 2°HPT or the basal plasma Ca2+ or phosphate levels. In rats with severe 2°HPT, the minimum plasma PTH level after NPS R-568 was greater than the basal level in mild 2°HPT. Thus, NPS R-568 is equally effective in suppressing plasma PTH and Ca2+ levels in rats with mild or severe renal or nutritional 2°HPT.

Plasma Levels of Parathyroid Hormone That Induce Anabolic )Effects in Bone of Ovariectomized Rats Can Be Achieved by Stimulation of Endogenous Hormone Secretion

Parathyroid hormone (PTH) administration increases bone mass in normal and osteopenic animals. However, this treatment currently requires the daily injection of large amounts of PTH, and the relationship of these doses to plasma levels of PTH that are achievable physiologically is unknown. We determined in ovariectomized (ovx) rats: 1) the plasma PTH levels that occur after the subcutaneous injection of graded doses of rat PTH, 2) whether similar PTH levels can be achieved by stimulation of endogenous PTH secretion, and 3) whether a plasma PTH profile that is achievable physiologically is anabolic on bone. Injection of 1, 5, or 25 micrograms/kg rat PTH-(1-34) increased plasma PTH by 46, 164, or 520 pg/mL, respectively, above basal levels within 60 min. Infusion of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N,N-tetraacetic acid for 2 h reduced plasma Ca2+ by 0.36 mmol/L and produced a total plasma PTH response (area under the plasma PTH curve) similar to that with the 5 micrograms/kg rat PTH injection. Then, 1, 5, or 25 micrograms/kg doses of rat PTH-(1-34) were injected subcutaneously daily for 28 days in 19-week-old rats that were ovx 7 weeks earlier. The 5 and 25 micrograms/kg doses significantly increased bone mineral density in the distal femur and trabecular bone area and average trabecular thickness in the proximal tibia. All doses of PTH significantly increased indices of trabecular connectivity and cancellous bone formation, including double-labeled surface, mineralizing surface, and surface-referent bone formation rate. In conclusion, anabolic effects on bone can be achieved with a plasma PTH profile similar to that attained following stimulation of the parathyroid gland by induced hypocalcemia. These data suggest that agents that transiently increase endogenous PTH secretion may represent a novel means to promote anabolic effects in skeletal tissues.

The parathyroid calcium receptor: a novel therapeutic target for treating hyperparathyroidism.

Parathyroid cells, C-cells, and certain cells in the kidney express a cell surface calcium (Ca2+) receptor which enables these cells to detect and respond to changes in the concentration of extracellular Ca2+. This receptor protein is a member of the G protein-coupled receptor superfamily and shares limited sequence homology only with metabotropic glutamate receptors. The Ca2+ receptor is the primary physiological mechanism regulating the secretion of parathyroid hormone (PTH) and plays a pivotal role in maintaining systemic Ca2+ homeostasis. Compounds that act as Ca2+ receptor agonists are called calcimimetics because they mimic or potentiate the effects of extracellular Ca2+ on parathyroid cell function. NPS R-568 is a small organic calcimimetic compound that acts as a positive allosteric modulator to increase the sensitivity of the Ca2+ receptor to activation by extracellular Ca2+. In normal rats, orally administered NPS R-568 decreases plasma levels of PTH and Ca2+ and, at higher doses, increases plasma levels of calcitonin. The changes in the circulating levels of these two hormones explain the hypocalcemia caused by this compound. NPS R-568 also effectively lowers plasma PTH levels in normal humans and in rat models of secondary hyperparathyroidism. Calcimimetic compounds that target the Ca2+ receptor provide a novel therapeutic approach for treating primary and secondary hyperparathyroidism.

The calcium receptor and calcimimetics.

Parathyroid cells can sense small changes in plasma Ca2+ levels by virtue of a cell surface Ca2+ receptor. Calcimimetics are newly synthesized compounds that act as agonists or positive allosteric modulators at the Ca2+ receptor and can suppress parathyroid hormone secretion. The first-generation calcimimetic, NPS R-568, has undergone clinical trials in primary hyperparathyroidism and in hyperparathyroidism secondary to chronic renal insufficiency. The data accumulated so far demonstrate that calcimimetics have potential as therapeutic agents for hyperparathyroidism and related bone diseases such as osteitis fibrosa.