Activation of the Calcium Receptor by Calcimimetic Agents is Preserved Despite Modest Attenuating Effects of Hyperphosphatemia

Background Some reports indicate that serum phosphorus levels in the range seen clinically among patients undergoing dialysis attenuate calcium receptor activation and modify parathyroid hormone (PTH) release from isolated parathyroid glands in vitro. Some clinicians and providers of dialysis thus have suggested that calcimimetic agents are ineffective and should not be used to manage secondary hyperparathyroidism among those undergoing dialysis when serum phosphorus concentrations exceed certain threshold levels. Methods To determine whether hyperphosphatemia diminishes the therapeutic response to calcimimetic agents, we used data from large clinical trials to analyze the effects of etelcalcetide and cinacalcet to lower plasma PTH levels in individuals on hemodialysis who had secondary hyperparathyroidism and varying degrees of hyperphosphatemia. Results Plasma PTH levels declined progressively during 26 weeks of treatment with either etelcalcetide or cinacalcet without regard to the degree of hyperphosphatemia at baseline. However, with each calcimimetic agent, the decreases in PTH from baseline were less at each interval of follow-up during the trials among participants with serum phosphorus levels above one of three prespecified threshold values compared with those with serum phosphorus levels below these thresholds. Conclusions These in vivo findings are the first in humans to support the idea that hyperphosphatemia attenuates calcium receptor activation by calcium ions and by calcimimetic agents. The effect of hyperphosphatemia on the responsiveness to calcimimetic agents appears relatively modest, however, and unlikely to be significant therapeutically. The efficacy of treatment with calcimimetic agents for lowering plasma PTH levels among those with secondary hyperparathyroidism remains robust despite substantial elevations in serum phosphorus.

The effect of evocalcet on vagus nerve activity of the gastrointestinal tract in miniature pigs

Evocalcet is a novel calcimimetic agent with fewer gastrointestinal (GI) adverse effects compared to cinacalcet. Although it is thought that cinacalcet induces GI side effects through the direct stimulation of the calcium receptor (CaR) expressed in the GI tract, the differences in the direct stimulatory effects of these two drugs on the GI tract have not been reported. In this study, we analyzed the difference in the GI effects of these two calcimimetic agents using miniature pigs by detecting vagus nerve stimulation after oral administration of the agents. Although cinacalcet induced vomiting in miniature pigs, evocalcet never induced emetic symptoms. A significant increase in the vagus nerve action potentials was observed after the administration of cinacalcet. Although the increase of that after the administration of evocalcet was mild and not significant in comparison to that in the vehicle group, it was not significantly different from the vagus nerve action potentials after cinacalcet treatment.

New Intravenous Calcimimetic Agents: New Options, New Problems. An Example on How Clinical, Economical and Ethical Considerations Affect Choice of Treatment

Background. Dialysis treatment is improving, but several long-term problems remain unsolved, including metabolic bone disease linked to chronic kidney disease (CKD-MBD). The availability of new, efficacious but expensive drugs (intravenous calcimimetic agents) poses ethical problems, especially in the setting of budget limitations. Methods. Reasons of choice, side effects, biochemical trends were discussed in a cohort of 15 patients (13% of the dialysis population) who stared treatment with intravenous calcimimetics in a single center. All patients had previously been treated with oral calcimimetic agents; dialysis efficacy was at target in 14/15; hemodiafiltration was employed in 10/15. Median Charlson Comorbidity Index was 8. The indications were discussed according to the principlist ethics (beneficience, non maleficience, justice and autonomy). Biochemical results were analyzed to support the clinical-ethical choices. Results. In the context of a strict clinical and biochemical surveillance, the lack of side effects ensured “non-maleficence”; efficacy was at least similar to oral calcimimetic agents, but tolerance was better. Autonomy was respected through a shared decision-making model; all patients appreciated the reduction of the drug burden, and most acknowledged better control of their biochemical data. The ethical conflict resides in the balance between the clinical “beneficience, non-maleficience” advantage and “justice” (economic impact of treatment, potentially in attrition with other resources, since the drug is expensive and included in the dialysis bundle). The dilemma is more relevant when a patient’s life expectancy is short (economic impact without clear clinical advantages), or when non-compliance is an issue (unclear advantage if the whole treatment is not correctly taken). Conclusions. In a context of person-centered medicine, autonomy, beneficence and non-maleficence should weight more than economic justice. While ethical discussions are not aimed at finding “the right answer” but asking “the right questions”, this example can raise awareness of the importance of including an ethical analysis in the choice of “economically relevant” drugs.

A model of calcium homeostasis in the rat

We developed a model of calcium homeostasis in the rat to better understand the impact of dysfunctions such as primary hyperparathyroidism and vitamin D deficiency on calcium balance. The model accounts for the regulation of calcium intestinal uptake, bone resorption, and renal reabsorption by parathyroid hormone (PTH), vitamin D3, and Ca2+itself. It is the first such model to incorporate recent findings regarding the role of the calcium-sensing receptor (CaSR) in the kidney, the presence of a rapidly exchangeable pool in bone, and the delayed response of vitamin D3synthesis. Accounting for two (fast and slow) calcium storage compartments in bone allows the model to properly predict the effects of bisphophonates on the plasma levels of Ca2+([Ca2+]p), PTH, and vitamin D3. Our model also suggests that Ca2+exchange rates between plasma and the fast pool vary with both sex and age, allowing [Ca2+]pto remain constant in spite of sex- and age-based hormonal and other differences. Our results suggest that the inconstant hypercalciuria that is observed in primary hyperparathyroidism can be attributed in part to counterbalancing effects of PTH and CaSR in the kidney. Our model also correctly predicts that calcimimetic agents such as cinacalcet bring down [Ca2+]pto within its normal range in primary hyperparathyroidism. In addition, the model provides a simulation of CYP24A1 inactivation that leads to a situation reminiscent of infantile hypercalcemia. In summary, our model of calcium handling can be used to decipher the complex regulation of calcium homeostasis.