Secondary Hyperparathyroidism: Pathophysiology and Treatment

Wissam Saliba, MD; Boutros El-Haddad, MD


J Am Board Fam Med. 2009;22(5):574-581. 

In This Article

Calcium and Phosphorus Homeostasis

The homeostasis of calcium and phosphorus is the result of complex relations between calcemia, phosphatemia, and different hormones and factors working synergistically to keep a normal balance of these minerals (Fig. 1).

Figure 1.

Normal calcium and phosphorus homeostasis. PTH, parathyroid hormone; FGF-23, fibroblasts growth factor 23.

Parathyroid Hormone

The parathyroid hormone (PTH) is the most important regulator of calcium metabolism. It is a polypeptide consisting of 84 amino acids and is secreted by the chief cells of the parathyroid glands in response to hypocalcemia and hyperphosphatemia. It has a short half-life (2 to 4 minutes) before being degraded to various inactive fragments. Although "intact" PTH assay is widely used to estimate active PTH level, it may react with some of its fragments. New assays, called "whole" PTH, have been recently developed for better measurement of full-length PTH.[3] PTH acts mainly on 2 organs: the bone and the kidney.

  1. It stimulates the osteoclasts and causes bone resorption, resulting in an increase in the serum concentration of calcium and phosphorus.

  2. PTH stimulates the 1-α hydroxylase activity in the kidney, resulting in an increase in 1,25 dihydroxyvitamin D production. It also increases the reabsorption of calcium in the distal renal tubules, decreasing calcium clearance. The effect on phosphorus clearance is the opposite. PTH can decrease the reabsorption of phosphorus in the proximal renal tubules from 85% in healthy individuals to less than 15% in dialysis patients.[4]

  3. Of note, PTH has no direct established activity on the intestine. However, it indirectly increases intestinal calcium and phosphorus absorption via stimulation of 1,25 dihydroxyvitamin D production. The results of high PTH are hypercalcemia, hypophosphatemia, and high urinary calcium and phosphorus.

  4. Calcium has a negative feedback effect on the parathyroid glands through the calcium sensing receptor.[5] Recently, phosphorus has been shown to have a direct stimulatory effect on the parathyroid glands.[6]

Vitamin D

Vitamin D is an essential factor in the regulation of calcium and phosphorus balance. It is synthesized in the skin but is also present in the diet. The active form is 1,25 dihydroxyvitamin D. Its main action is to enhance the availability of calcium and phosphorus for new bone formation. Recent studies have also shown important actions of vitamin D in many other tissues. Vitamin D enhances the intestinal absorption of calcium and phosphorus, increasing their serum levels.

  1. Along with PTH, vitamin D is a required factor in the bone resorption process.

  2. It also increases the reabsorption of urinary calcium and phosphorus in the renal tubules.

  3. Through the vitamin D receptors it has a direct effect on the parathyroid glands to suppress PTH secretion.[7]

Fibroblasts Growth Factor-23

Until recently, it was thought that the phosphorus homeostasis was mainly achieved by PTH and vitamin D. Recent studies identified fibroblasts growth factor (FGF)-23 as a new protein with phosphaturic activity. It is mainly secreted by osteocytes and is now considered to be the most important factor for regulation of phosphorus homeostasis.

  1. Through the Klotho receptor it acts mainly on the kidney to increase phosphorus clearance.[8]

  2. FGF-23 also inhibits the 1-α hydoxylase activity, causing a low 1,25 dihydroxyvitamin D level.

  3. Hyperphosphatemia is the principal stimulator for FGF-23.

  4. It is not yet proven if there is any direct relation between PTH and FGF-23.