What is the relationship between parathyroid hormone (PTH), calcium levels, and vitamin D 25-hydroxy in patients with concerns about calcium regulation and potential parathyroid disorders?

Relationship Between PTH, Calcium, and Vitamin D 25-Hydroxy

The Fundamental Regulatory Axis

PTH, calcium, and vitamin D 25-hydroxy form a tightly integrated feedback loop where hypocalcemia triggers PTH release, which then stimulates conversion of 25-hydroxyvitamin D to the active 1,25-dihydroxyvitamin D form, ultimately increasing calcium absorption and normalizing serum calcium levels. 1

How the System Works Under Normal Conditions

• Hypocalcemia is sensed via the calcium-sensing receptor on parathyroid glands, resulting in PTH release 1

• PTH increases calcium concentration through three mechanisms: 1

  • First, PTH stimulates the enzyme 1-α-hydroxylase (CYP27B1) to convert 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D, which increases intestinal calcium absorption 1
  • Second, PTH binding to PTH1R in the distal and proximal renal tubule increases calcium reabsorption and decreases phosphate reabsorption 1
  • Third, PTH binding to PTH1R in bones stimulates release of calcium and phosphate from bone into circulation 1

• The active vitamin D metabolite 1,25-dihydroxyvitamin D provides negative feedback by suppressing PTH synthesis in parathyroid glands through the vitamin D receptor (VDR) 1, 2

• Both calcium and vitamin D metabolites can decrease PTH secretion—calcium through the calcium-sensing receptor and 1,25-dihydroxyvitamin D through the VDR 3

The Critical Role of 25-Hydroxyvitamin D

• 25-hydroxyvitamin D is the substrate that PTH acts upon—without adequate 25-hydroxyvitamin D levels, PTH cannot effectively increase calcium absorption regardless of how elevated PTH becomes 1
• Active calcium absorption decreases when serum 25-hydroxyvitamin D concentration falls below 20 nmol/L (approximately 8 ng/mL) 3
• With increasing serum 25-hydroxyvitamin D concentration up to 100 nmol/L (40 ng/mL) or higher, serum PTH continues to decrease 3

Pathological States That Disrupt This Relationship

Vitamin D Deficiency and Secondary Hyperparathyroidism

• When 25-hydroxyvitamin D levels are low, PTH rises compensatorily (secondary hyperparathyroidism) in an attempt to maintain calcium homeostasis 1, 4
• In chronic kidney disease patients with GFR <60 mL/min/1.73 m² (Stage 3), secondary hyperparathyroidism with elevated PTH is common despite normal or low-normal plasma 1,25-dihydroxyvitamin D levels 1
• Normal 1,25-dihydroxyvitamin D levels in the face of high PTH are inappropriate and contribute to defective feedback suppression of PTH synthesis 1
• A low calcium intake aggravates the consequences of vitamin D deficiency, demonstrating the interaction between vitamin D and calcium 3

Primary Hyperparathyroidism

• In primary hyperparathyroidism, PTH is autonomously elevated despite hypercalcemia, representing a failure of the normal calcium-PTH feedback loop 5, 6
• Patients with primary hyperparathyroidism have elevated plasma 1,25-dihydroxyvitamin D levels (increased by 27% compared to controls) due to PTH-driven conversion of 25-hydroxyvitamin D 6
• However, 1,25-dihydroxyvitamin D still suppresses PTH even in primary hyperparathyroidism—when 1,25-dihydroxyvitamin D levels decrease, PTH levels reciprocally increase despite consistent calcium levels 2
• Serum total 25-hydroxyvitamin D levels are often lower in primary hyperparathyroidism patients, though free and bioavailable 25-hydroxyvitamin D may remain similar to controls 7
• Intact PTH levels are inversely correlated with free (r = -0.217) and bioavailable 25-hydroxyvitamin D levels (r = -0.296) even in primary hyperparathyroidism 7

Familial Hypocalciuric Hypercalcemia vs. Primary Hyperparathyroidism

• Both conditions present with elevated calcium and normal or elevated PTH, but primary hyperparathyroidism patients have significantly higher PTH and 1,25-dihydroxyvitamin D levels compared to familial hypocalciuric hypercalcemia patients, despite similar calcium and 25-hydroxyvitamin D levels 8

Clinical Implications and Measurement Pitfalls

PTH Assay Variability

• PTH assays differ in antibodies used and consequently measure different extents of PTH fragments and isoforms in addition to biologically active PTH 1
• Lack of standardization leads to remarkable differences in PTH concentrations measured in different laboratories—PTH measurements can vary up to 47% between different assay generations 1, 5
• PTH is most stable in EDTA plasma rather than serum and at 4°C rather than room temperature 5
• Biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant 5

Factors Affecting the Relationship

• In primary hyperparathyroidism, plasma 1,25-dihydroxyvitamin D depends positively on renal function and female sex but inversely on body mass index and plasma phosphate 6
• A high calcium intake increases the half-life of 25-hydroxyvitamin D, while in patients with primary or secondary hyperparathyroidism, the half-life of 25-hydroxyvitamin D is shorter 3
• Vitamin D is not needed for paracellular calcium transport, which depends on the calcium gradient, but is essential for active transcellular calcium transport 3

Therapeutic Considerations

• In chronic kidney disease Stage 3, administration of small doses of active vitamin D sterols (calcitriol 0.25 μg/day or alfacalcidol 0.25-0.5 μg/day) reduces PTH levels and improves bone histology without worsening kidney function 1
• However, active vitamin D analogs should never be used to treat nutritional vitamin D deficiency, as they bypass normal regulatory mechanisms and do not correct 25-hydroxyvitamin D levels 9, 4
• Cinacalcet, a calcimimetic agent, directly lowers PTH by increasing calcium-sensing receptor sensitivity to extracellular calcium, with PTH reduction associated with concomitant decrease in serum calcium 10