Hyperparathyroidism therapy with cinacalcet

The tiny parathyroid glands are located in the neck and are usually located adjacent to the thyroid gland, hence the term “parathyroid”. There are usually four parathyroid glands, but there can be more, and they can sometimes lie in locations away from the thyroid, sometimes elsewhere in the neck or even in the chest (mediastinum).

The parathyroid glands secrete parathyroid hormone (PTH), which is required to regulate serum calcium levels. The intact form of PTH can be measured in the serum and is termed “iPTH”. Ionized (free) calcium binds to calcium ‘receptors’ on the surface of parathyroid cells, raising the concentration of calcium in the parathyroid cell and inhibiting PTH secretion by the cell. If the serum ionized calcium concentration is low, PTH secretion is increased and increases serum calcium. PTH increases serum calcium by several effects: 1) PTH acts upon the kidney tubules to increase calcium reabsorption by the kidney tubule filtrate heading towards urinary excretion. 2) PTH acts upon bones to release calcium. 3) PTH acts upon the kidney cells to convert more 25-hydroxy-vitamin D to the active 1,25-dihydroxy-vitamin D; this active vitamin D stimulates the intestines to absorb more calcium from food.

The term “hyperparathyroidism” refers to the any condition in which the serum level of intact parathyroid hormone is above the range of normal for healthy individuals. The term “secondary hyperparathyroidism” can refer to the normal increase in serum PTH levels that are seen with calcium deficiency, usually caused by vitamin D deficiency. Vitamin D deficiency is common and is caused by inadequate sun exposure producing less vitamin D3 in the skin and inadequate dietary intake of vitamin D3 and vitamin D2. Secondary hyperparathyroidism also occurs in renal failure when the kidneys fail to excrete phosphate in the urine, causing high serum levels of phosphate that combine with serum calcium to reduce the serum concentration of free calcium that can bind to the parathyroid glands’ calcium receptors, thus causing the parathyroid glands to secrete excessive PTH, resulting in a bone disease called “renal osteodystrophy”. In renal failure, the parathyroid glands can become very large and autonomous and continue to secrete excessive amounts of PTH even after serum phosphate levels are normalized by kidney transplant or oral phosphate-binding resins, a condition known as “tertiary hyperparathyroidism”.

“Primary hyperparathyroidism” refers to excessive secretion of PTH in the absence of the conditions noted above. Primary hyperparathyroidism is usually caused by a benign overgrowth of one parathyroid gland, resulting in a “parathyroid adenoma”. Sometimes, several parathyroid glands become overactive, particularly in conditions such as Multiple Endocrine Neoplasia or in familial hyperparathyroidism in which there is a defect in the parathyroid glands’ calcium-sensing mechanism.

In primary hyperparathyroidism, excessive PTH over-stimulates bones, resulting in bone and joint pain. Serum calcium levels are usually high, resulting in high calcium concentrations in the glomerular filtrate that overwhelms the kidney tubules’ ability to reabsorb calcium, resulting in hypercalciuria and an increased risk for the development of calcium kidney stones. Mild hyperparathyroidism can be asymptomatic and in such cases it must be distinguished from “benign hypocalciuric hypercalcemia” (BHH) in which condition the renal excretion of calcium is very low; BHH is benign and requires no therapy. Hypercalcemia can cause increased thirst and urination, anorexia, abdominal pains, nausea, weight loss, skin itching, constipation, fatigue, intellectual weariness, depression, anemia, and hypertension. People with hyperparathyroidism can also experience muscle weakness, paresthesias, psychosis, and even coma. Pancreatitis can also occur.

Treatment of hyperparathyroidism is tailored to the cause. In secondary hyperparathyroidism due to vitamin D deficiency, oral vitamin D is given, sometimes in large doses. It is prudent to administer vitamin D supplements of at least 800 U daily to people who are homebound and do not get at least 10-15 minutes of unprotected sun exposure daily. In renal failure, oral phosphate-binding resins (e.g., PhosLo) are given orally with each meal to reduce the intestinal absorption of dietary phosphate and prevent hyperphosphatemia. Patients with renal failure on dialysis are administered a synthetic vitamin D analogue medication that inhibits the parathyroid glands’ secretion of PTH but doesn’t cause excessive calcium absorption from the intestine; paracalcitol (Zemplar) is often used and is given intravenously during dialysis in doses of 0.04-0.1 mcg/kg body weight 3X weekly. Possible side-effects of paracalcitol hypercalcemia as well as nausea, vomiting, edema, chills, fever, flu-like symptoms, light-headedness, palpitations, and dry mouth; sepsis and GI bleeding have also been rarely reported as side effects from paricalcitol. Doxercalciferol (Hectorol) can also be used to inhibit PTH secretion. Doxercalciferol has the advantage of being administered orally, starting with 10 mcg orally 3X weekly when serum iPTH levels are over 400 pg/mL (42 pmol/L); it can cause hypercalcemia, headache, malaise, malaise, myalgias, bone pain, constipation, a metallic taste, nausea, and vomiting.

Treatment of primary hyperparathyroidism has been neck surgery, ideally by a surgeon specializing in endocrine surgery. Preoperatively, parathyroid adenomas can often be visualized in the neck with ultrasound and sestamibi scanning. With such identification, a limited neck exploration can be performed, with an introperative serum iPTH measurement being done to confirm the removal of all the abnormal tissue. Postoperatively, serum calcium levels can drop very low, resulting in paresthesias or severe muscle spasms (“tetany”), since the remaining normal parathyroid glands have been suppressed by the hypercalcemia and require time to recover. Therefore, it is prudent to admit patients overnight following parathyroid surgery and administer calcium supplements prophylactically, once hypercalcemia has resolved.

Cinacalcet (Sesipar) is a “calcimimetic” medication that looks like calcium to the calcium-sensing receptor on the parathyroid cells; administration of cinacalcet causes the parathyroid glands to reduce their secretion of PTH. Cinacalcet was administered to 665 patients with kidney failure who were receiving dialysis: A reduction (at least 30%) in serum iPTH was seen in 62% of patients receiving cinacalcet, compared with 11% in patients receiving placebo. Patients’ vitamin D analogues and phosphate binders were continued during the study. Cinacalcet is given orally, starting with 30 mg daily and titrating the dose upward to 60 mg/day or 90 mg/day, the mean dose being 60 mg/day. Side effects included occasional nausea and vomiting, leading to withdrawal in 7% of the patients receiving cinacalet and 2% of those receiving placebo.

Cinacalcet has therapeutic applications beyond treating the secondary hyperparathyroidism of renal failure. Cinacalcet may be useful as an alternative to surgery for patients with primary hyperparathyroidism. (Shoback DM, et al: J Clin Endocrinol Metab 88:5644-5649, 2003) In the latter study, cinacalcet was generally well-tolerated, although 2 of 9 patients did complain of some symptoms that may have been due to cinacalcet: asthenia, dizziness, headache, and fatigue. Cinacalcet may be particularily useful for patients who have multi-gland involvement (e.g., familial hyperparathyroidism, multiple endocrine neoplasia) as an alternative to surgery. Surgery for patients with multi-gland involvement is often unsuccessful, since surgery requires the removal of 3 complete parathyroid glands and half of a fourth gland; relapse is common, as is permanent hypoparathyroidism. Cinacalcet can also be used to treat the severe life-threatening hypercalcemia that occurs in patients with parathyroid carcinoma.

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