Parathyroid hormone (PTH) is released by four small glands in the neck and serves as the body’s primary regulator of calcium and phosphate balance. PTH maintains a tightly controlled level of calcium in the bloodstream, a mineral required for essential functions like nerve signaling and muscle contraction. When kidney function declines due to chronic disease, this hormonal balance is severely disrupted. This disruption leads to excessive PTH production and a complex disorder of mineral and bone metabolism, causing systemic health issues in patients with advanced kidney disease.
PTH’s Normal Function in Calcium Regulation
The main physiological role of PTH is to rapidly increase blood calcium levels when they fall below a healthy range. The parathyroid glands monitor calcium concentrations using specialized calcium-sensing receptors (CaSRs) on their surface. When these receptors detect a drop in circulating calcium, they signal the glands to release PTH into the bloodstream.
PTH acts on three main target organs: the bones, the kidneys, and the intestines. In the bones, PTH stimulates bone-resorbing cells called osteoclasts to release calcium and phosphate into the circulation. Simultaneously, PTH acts on the kidneys to increase calcium reabsorption, preventing its loss in the urine, while promoting phosphate excretion.
The kidney also plays a specialized role in activating Vitamin D, a process PTH directly influences. PTH stimulates the enzyme 1-alpha-hydroxylase, which converts inactive Vitamin D into its highly potent form, calcitriol (1,25-dihydroxyvitamin D). Calcitriol then travels to the intestines where it increases the absorption of both calcium and phosphate from ingested food, completing the homeostatic loop that stabilizes blood calcium levels.
Why PTH Increases When Kidneys Fail
Chronic kidney disease (CKD) progressively impairs the kidney’s ability to maintain mineral balance, triggering secondary hyperparathyroidism, marked by excessive PTH production. This overproduction is driven by two interrelated mechanisms that occur as the glomerular filtration rate (GFR) steadily declines.
The first mechanism involves the body’s inability to effectively excrete phosphate, resulting in phosphate retention, or hyperphosphatemia. As the kidneys lose function, rising phosphate levels directly stimulate the parathyroid glands to produce more PTH. The rising phosphate levels also stimulate the production of Fibroblast Growth Factor 23 (FGF23), a hormone released by bone cells.
FGF23 acts on the kidney to increase phosphate excretion, but it also inhibits the enzyme 1-alpha-hydroxylase. This inhibition represents the second primary mechanism driving secondary hyperparathyroidism: impaired Vitamin D activation. Since the failing kidneys already have a reduced capacity to produce the enzyme, high levels of FGF23 further suppress the conversion of inactive Vitamin D into active calcitriol.
The resulting lack of active calcitriol limits the amount of calcium the intestine can absorb from the diet. This leads to low blood calcium levels (hypocalcemia), which is a powerful signal that further stimulates the parathyroid glands to release even more PTH. Over time, the glands become pathologically enlarged and hyperactive, a process called hyperplasia, making them less responsive to normal feedback loops and perpetuating the cycle of excessive PTH secretion.
Complications Stemming from High PTH Levels
The long-term consequence of chronically high PTH levels is damaging effects, particularly on the skeletal and cardiovascular systems. High PTH leads to renal osteodystrophy, a specific form of bone disease encompassing various structural abnormalities in the skeleton. The most common form is osteitis fibrosa cystica, also known as high-turnover bone disease, which is directly caused by the bone-resorbing activity of PTH.
In this condition, excess PTH continuously pulls calcium and phosphate out of the bone matrix to maintain blood calcium levels. This results in weakened, porous bones that are prone to pain and spontaneous fractures. The structural integrity of the bone is compromised because bone destruction outpaces the body’s ability to rebuild it effectively. In severe, advanced cases, this bone remodeling leads to physical changes, including bone pain, muscle weakness, and joint discomfort.
Another severe complication is extraskeletal calcification, where calcium and phosphate deposit in soft tissues outside the skeleton. High concentrations of these minerals form complexes that lodge primarily within the walls of blood vessels. This process, known as vascular calcification, stiffens the arteries and makes them less elastic, significantly raising the risk of high blood pressure and cardiovascular events. Since cardiovascular disease is the leading cause of death in CKD patients, the high PTH-driven mineral disorder contributes directly to patient mortality. Systemic effects can also manifest as persistent itching (uremic pruritus) and fatigue.
Treatment Approaches for PTH Management
Managing secondary hyperparathyroidism requires restoring mineral balance and suppressing the overactive parathyroid glands. Dietary intervention involves restricting the intake of phosphate-rich foods. Since the failing kidney cannot remove phosphate, limiting its entry into the body is necessary to prevent hyperphosphatemia.
To control phosphate levels, patients are prescribed phosphate binders, which are medications taken with meals. These agents work locally in the gastrointestinal tract, binding to ingested phosphate and preventing its absorption into the bloodstream, allowing it to be excreted in the stool. Common examples include calcium-based binders or non-calcium-containing binders such as sevelamer.
A direct pharmacological approach involves the use of calcimimetics, drugs designed to target the parathyroid gland’s calcium-sensing receptor (CaSR). These compounds act as positive allosteric modulators, effectively mimicking the action of calcium. This action makes the parathyroid gland more sensitive to the calcium already present in the blood. By activating the CaSR, calcimimetics rapidly suppress the release of PTH.
Another therapeutic strategy is the use of active Vitamin D analogs, which are synthetic versions of calcitriol. These analogs directly suppress PTH production by binding to Vitamin D receptors found on the parathyroid cells, bypassing the need for kidney activation. Active Vitamin D therapy is useful because it helps normalize the low calcitriol levels seen in CKD, but it must be used cautiously as it can raise both calcium and phosphate levels. For patients with severe, persistently uncontrolled secondary hyperparathyroidism and massively enlarged glands, a surgical procedure known as parathyroidectomy may be necessary as a final option to remove the overactive tissue.