Parathyroid hormone (PTH) is a polypeptide hormone produced by four small parathyroid glands located in the neck. Its primary function is to maintain calcium concentration in the bloodstream within a narrow, healthy range. Calcium is necessary for numerous bodily functions, including nerve impulse transmission, muscle contraction, and maintaining the structural integrity of the skeletal system. When blood calcium levels begin to drop, the parathyroid glands release PTH to quickly restore balance.
PTH’s Direct Action on Bone and Kidneys
Parathyroid hormone directly targets the skeleton and the kidneys to elevate circulating calcium levels. In the bone, PTH acts to mobilize the vast calcium reserves stored within the mineral matrix. It does this indirectly by binding to receptors on osteoblasts, the cells responsible for building bone.
Upon stimulation, osteoblasts release signaling molecules, notably the Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL), and reduce Osteoprotegerin (OPG) secretion. This shift in the RANKL/OPG ratio stimulates osteoclast precursor cells to mature into active osteoclasts, which resorb bone tissue. These osteoclasts then break down the mineralized bone matrix, releasing both calcium and phosphate ions into the bloodstream.
In the kidneys, PTH executes two simultaneous actions to adjust mineral balance. First, it acts on the distal convoluted tubules of the nephrons to increase the reabsorption of calcium from the filtered fluid back into the blood. This action is mediated by upregulating the transient receptor potential vanilloid-5 (TRPV5) calcium channels, effectively preventing calcium loss in the urine.
Second, PTH promotes the excretion of phosphate by inhibiting its reabsorption in the proximal convoluted tubules. It achieves this by downregulating the sodium-phosphate co-transporter (Npt2a). This phosphaturic effect prevents the newly released phosphate from binding with calcium in the blood, which would otherwise decrease the concentration of free, biologically active calcium.
PTH’s Role in Vitamin D Activation
Beyond its direct actions, PTH plays a significant role in calcium homeostasis by regulating the activation of Vitamin D. This represents an indirect mechanism for increasing blood calcium concentrations. PTH stimulates the enzyme 1-alpha-hydroxylase, which is located primarily in the kidney’s proximal tubules.
This enzyme converts the inactive storage form of Vitamin D, 25-hydroxyvitamin D (calcidiol), into its biologically active form, 1,25-dihydroxyvitamin D (calcitriol). Calcitriol is functionally a steroid hormone and is the most potent promoter of calcium uptake from the diet.
Once activated by PTH, calcitriol travels to the small intestine, where it significantly enhances the absorption of dietary calcium. This intestinal action provides a sustained influx of calcium into the body.
The Regulatory Feedback Loop
The body maintains calcium balance through a negative feedback system that governs PTH release. The parathyroid glands act as the sensing mechanism for blood calcium concentration via specialized proteins called Calcium-Sensing Receptors (CaSRs) situated on the cell surface.
When the calcium level dips below the normal set point, the CaSRs are less activated, signaling the parathyroid cells to synthesize and release PTH. The secreted PTH then initiates its actions on bone, kidneys, and Vitamin D activation to raise the calcium level.
As PTH successfully increases calcium concentration, the elevated calcium ions bind more frequently to the CaSRs. This binding signals the parathyroid cells to suppress PTH secretion. This loop ensures PTH is only released when necessary and is quickly withdrawn once calcium homeostasis is achieved.
Consequences of PTH Imbalance
When PTH secretion is disrupted, it alters calcium levels. An overproduction of PTH, known as hyperparathyroidism, leads to persistently high blood calcium (hypercalcemia). This chronic elevation often results in excessive bone resorption, causing bone pain and increasing the risk of fractures.
Hypercalcemia also increases the filtered load of calcium in the kidneys, frequently leading to the formation of calcium-containing kidney stones. Conversely, insufficient PTH production, called hypoparathyroidism, results in low blood calcium (hypocalcemia). This deficiency causes neuromuscular symptoms, such as muscle spasms, cramps, and tingling sensations in the extremities, due to the destabilization of nerve and muscle cell membranes.