Cinacalcet, known by the brand name Sensipar, is an oral medication that manages conditions linked to overactive parathyroid glands. It belongs to a class of agents called calcimimetics. Cinacalcet addresses imbalances in mineral metabolism, particularly in patients with chronic kidney disease.
Parathyroid Gland and Calcium Imbalance
Four small parathyroid glands, located in the neck near the thyroid, regulate blood calcium and phosphorus levels by secreting parathyroid hormone (PTH). When blood calcium decreases, PTH release increases to elevate calcium. Conversely, high calcium suppresses PTH secretion, maintaining a delicate balance.
Secondary hyperparathyroidism, common in chronic kidney disease (CKD), disrupts this balance. As kidney function declines, the body struggles to excrete phosphorus, leading to increased blood phosphorus. Impaired kidneys also produce less active vitamin D, needed for calcium absorption, resulting in lower blood calcium.
These disruptions—high phosphorus and low calcium—chronically stimulate the parathyroid glands. This constant stimulation can cause the glands to enlarge and produce excessive PTH, even when calcium levels are normal or elevated, breaking the normal feedback loop. This overproduction of PTH contributes to bone and mineral disorders, a serious complication of CKD.
The Calcium-Sensing Receptor
The calcium-sensing receptor (CaSR) is a protein on the surface of parathyroid gland cells. This receptor functions as a molecular sensor, constantly monitoring blood calcium concentration. When calcium binds to the CaSR, it signals parathyroid cells to decrease parathyroid hormone production and release.
This signaling mechanism is fundamental for maintaining calcium homeostasis. The CaSR integrates various aspects of parathyroid gland function, including gene transcription and cell proliferation. Its activation influences the rate at which PTH is synthesized and secreted by the parathyroid cells.
In secondary hyperparathyroidism, the CaSRs in the parathyroid glands can become less responsive to circulating calcium. This reduced sensitivity means that even with adequate calcium levels, the receptors do not effectively signal the glands to reduce PTH production, contributing to persistent parathyroid gland overactivity. The impaired function of these receptors allows for continued PTH secretion, perpetuating the mineral imbalance.
How Cinacalcet Functions as a Calcimimetic
Cinacalcet is a calcimimetic agent, meaning it “mimics” the effects of calcium on specific tissues, particularly on the calcium-sensing receptors. This drug directly lowers parathyroid hormone (PTH) levels by increasing the sensitivity of the calcium-sensing receptors (CaSRs) to extracellular calcium. It achieves this by binding to the CaSR at an allosteric binding site, distinct from where calcium typically binds.
The binding of cinacalcet to this allosteric site induces a conformational change in the CaSR protein. This alteration makes the receptor more responsive to existing blood calcium levels, enhancing its ability to detect and react to calcium. By doing so, cinacalcet “tricks” the parathyroid gland into perceiving a higher calcium concentration than actually exists.
This heightened sensitivity to calcium restores the parathyroid gland’s natural feedback mechanism. Even with calcium levels that might otherwise trigger PTH release, the cinacalcet-bound receptor signals for reduced hormone secretion. This mechanism allows for more effective suppression of PTH production, addressing glandular overactivity.
Therapeutic Outcomes of Lowering PTH
The action of cinacalcet directly leads to a reduction in parathyroid hormone (PTH) secretion from overactive glands. Studies show cinacalcet treatment can achieve at least a 30% reduction in PTH levels in most patients with secondary hyperparathyroidism, with an overall mean reduction of approximately 38%. This PTH suppression is the primary goal of therapy, aiming to bring hormone levels closer to a healthy range.
Lower PTH levels bring about several beneficial effects on mineral metabolism. A reduction in PTH typically leads to a decrease in blood calcium levels, as PTH promotes calcium release from bones and reabsorption in the kidneys. Additionally, lower PTH can contribute to a decrease in blood phosphorus levels, important for patients with chronic kidney disease.
Correcting these mineral imbalances helps manage the bone disease associated with secondary hyperparathyroidism, known as renal osteodystrophy. By reducing excessive bone breakdown and mitigating calcium and phosphorus buildup, cinacalcet supports bone health and can help prevent complications like vascular calcification. This improved mineral balance contributes to the overall well-being of patients.