ronacaleret and Hypercalcemia

Ronacaleret is an orally-active calcium-sensing receptor (CaSR) antagonist that has the potential for therapeutic utility in the stimulation of PTH release, notably as a bone anabolic agent comparable to recombinant human PTH(1-34) (rhPTH(1-34)). A recent study has shown that, despite the ability to increase circulating PTH levels in postmenopausal women in a dose-dependent manner, minimal effects of ronacaleret on bone mineral density have been observed. Therefore, the purpose of this study was to characterize the PTH profile as well as calcium metabolism parameters as a marker of PTH biological activity following the administration of ronacaleret or rhPTH(1-34). Administration of ronacaleret led to lower peak levels of PTH than were observed with rhPTH(1-34), however, greater total PTH exposure was observed. Further, chronic administration of either agent was associated with increases in urinary calcium excretion and serum calcium levels, with the magnitude of the changes following ronacaleret significantly greater than that for rhPTH(1-34). The greater magnitude of effects observed with ronacaleret is likely due to the greater total PTH exposure, and is potentially reflective of a state comparable to mild hyperparathyroidism. It is not clear whether the administration of all calcilytics would lead to a similar result, or is due to characteristics specific to ronacaleret.

Topics: Adult; Aged; Calcium; Demography; Female; Humans; Hypercalcemia; Indans; Kidney; Middle Aged; Parathyroid Hormone; Peptide Fragments; Phenylpropionates; Phosphates; Postmenopause; Procollagen; Receptors, Calcium-Sensing; Time Factors

Acute hypercalcemia inhibits plasma renin activity (PRA). How this occurs is unknown. We hypothesized that acute hypercalcemia inhibits PRA via the calcium-sensing receptor because of parathyroid hormone-mediated increases in renal cortical interstitial calcium via TRPV5. To test our hypothesis, acute in vivo protocols were run in sodium-restricted, anesthetized rats. TRPV5 messenger RNA expression was measured with real-time quantitative RT-PCR. Acute hypercalcemia significantly decreased PRA by 37% from 32.0±3.3 to 20.3±2.6 ng of angiotensin I per milliliter per hour (P<0.001). Acute hypercalcemia also significantly increased renal cortical interstitial calcium by 38% (1.73±0.06 mmol/L) compared with control values (1.25±0.05 mmol/L; P<0.001). PRA did not decrease in hypercalcemia in the presence of a calcium-sensing receptor antagonist, Ronacaleret (22.8±4.3 versus 21.6±3.6 ng of angiotensin I per milliliter per hour). Increasing plasma calcium did not decrease PRA in parathyroidectomized rats (22.5±2.6 versus 22.0±3.0 ng of angiotensin I per milliliter per hour). Parathyroidectomized rats were unable to increase their renal cortical interstitial calcium in response to hypercalcemia (1.01±0.11 mmol/L). Acutely replacing plasma parathyroid hormone levels did not modify the hypercalcemic inhibition of PRA in parathyroid-intact rats (39.1±10.9 versus 16.3±3.2 ng of angiotensin I per milliliter per hour; P<0.05). Renal cortical TRPV5 messenger RNA expression decreased by 67% in parathyroidectomized (P<0.001) compared with intact rats. Our data suggest that acute hypercalcemia inhibits PRA via the calcium-sensing receptor because of parathyroid hormone-mediated increases in renal cortical interstitial calcium via TRPV5.

Topics: Angiotensin I; Animals; Calcium; Calcium Channels; Hypercalcemia; Indans; Kidney; Male; Models, Animal; Parathyroid Hormone; Parathyroidectomy; Phenylpropionates; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing; Renin; RNA, Messenger; Signal Transduction; TRPV Cation Channels