What is the relationship between calcium and parathyroid hormone (PTH)?

Calcium and Parathyroid Hormone: A Negative Feedback Regulatory System

Calcium and parathyroid hormone (PTH) exist in an inverse relationship where low serum calcium triggers PTH release from the parathyroid glands, and PTH then acts to restore calcium levels through three coordinated mechanisms: increasing renal calcium reabsorption, stimulating bone calcium release, and enhancing intestinal calcium absorption via vitamin D activation. 1

The Calcium-Sensing Mechanism

The parathyroid glands detect changes in serum calcium through the calcium-sensing receptor (CaSR) located on the surface of chief cells. 2 This receptor serves as the principal regulator of PTH synthesis and secretion, functioning as a molecular "thermostat" for calcium homeostasis. 2, 3

• Hypocalcemia is sensed via the CaSR, resulting in immediate PTH release from the parathyroid glands 1
• The secretory response occurs within minutes of calcium changes, with PTH levels rising to 396% of baseline in normal individuals during induced hypocalcemia 4
• Conversely, hypercalcemia suppresses PTH secretion, with levels falling to 24% of baseline within 30 minutes of calcium infusion in healthy subjects 4

PTH's Three-Pronged Mechanism to Raise Calcium

1. Renal Effects (Immediate Action)

PTH binding to PTH1R in the kidney increases calcium reabsorption while simultaneously decreasing phosphate reabsorption. 1, 5

• In the proximal tubule, PTH decreases sodium reabsorption, which indirectly reduces paracellular calcium reabsorption, but this is offset by effects in distal segments 5
• In the thick ascending limb (TAL), PTH increases calcium permeability and the electrical driving force, enhancing calcium reabsorption 5
• In the distal convolution, PTH increases transcellular calcium reabsorption by increasing activity and abundance of the TRPV5 calcium channel 5
• The net effect is increased urinary calcium retention and increased phosphate excretion (phosphaturia) 1, 5

2. Vitamin D Activation (Hours to Days)

PTH stimulates the enzyme 1-α-hydroxylase (CYP27B1) in the kidney to convert 25-hydroxyvitamin D into the active form 1,25-dihydroxyvitamin D. 1

• 1,25-dihydroxyvitamin D then binds to vitamin D receptors (VDR) in the intestine, increasing intestinal calcium absorption 1
• This represents a slower but sustained mechanism for calcium restoration 6

3. Bone Mobilization (Hours to Days)

PTH binding to PTH1R in bone stimulates the release of both calcium and phosphate from bone into the circulation. 1

• This occurs through increased osteoclastic bone resorption 6
• While effective at raising calcium, chronic elevation leads to high-turnover bone disease with abnormal bone resorption, formation, and marrow fibrosis 7

The Negative Feedback Loop Completion

Once PTH successfully raises serum calcium levels through these mechanisms, the elevated calcium is detected by the CaSR on parathyroid cells, which then suppresses further PTH secretion, completing the negative feedback loop. 1, 3

• The relationship between calcium and PTH follows a sigmoidal curve, with a "set-point" (the calcium concentration causing half-maximal PTH suppression) of approximately 1.21 mmol/L in healthy individuals 4
• PTH has a very short plasma half-life of 2-4 minutes, allowing for rapid adjustments to calcium fluctuations 1

Clinical Implications and Pathophysiology

In Chronic Kidney Disease

The calcium-PTH relationship becomes disrupted in CKD due to multiple factors: 1

• Phosphate retention occurs early, causing transient hypocalcemia that stimulates PTH release 1
• Impaired vitamin D activation reduces intestinal calcium absorption and removes direct suppression of PTH 1
• Decreased expression of calcium-sensing receptors on parathyroid glands makes them resistant to calcium's suppressive effects 1
• The result is secondary hyperparathyroidism, where PTH remains elevated despite normal or even elevated calcium levels 1, 7

Important Caveats

• In hyperparathyroid states (primary or secondary), the set-point for calcium-regulated PTH secretion may be shifted, though research shows this shift is less pronounced than previously thought 4, 8
• The ratio of PTH fragments to full-length PTH changes with calcium concentration—hypocalcemia decreases this ratio while hypercalcemia increases it 1
• Calcimimetic agents like cinacalcet work by increasing the sensitivity of the CaSR to calcium, thereby lowering PTH without actually raising calcium levels 2

The Phosphate Connection

While PTH raises calcium, it simultaneously lowers serum phosphate through increased renal excretion. 1, 7 This prevents the calcium-phosphorus product from rising excessively, which would otherwise lead to soft tissue calcification. 7 This phosphaturic effect is critical in early CKD to maintain normal phosphate levels, but fails when GFR falls below 20-30 mL/min/1.73 m². 7