What is the function of Parathyroid Hormone (PTH) and what are the related disease conditions and treatments?

Function of Parathyroid Hormone, Related Diseases, and Treatments

Parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney, functioning through binding to specific high-affinity cell-surface receptors to maintain calcium homeostasis through actions on bone remodeling, renal tubular reabsorption, and intestinal calcium absorption. 1

Physiological Functions of PTH

• PTH regulates calcium and phosphate homeostasis through actions on multiple target organs including bone, kidney, and indirectly the intestines 1, 2
• In the kidney, PTH increases calcium reabsorption while decreasing phosphate reabsorption, creating a phosphaturic effect that helps maintain normal serum phosphate levels 3
• PTH stimulates the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, enhancing intestinal calcium absorption 3, 2
• In bone, PTH stimulates bone remodeling with preferential stimulation of osteoblastic activity over osteoclastic activity when administered intermittently 1
• The skeletal effects of PTH depend on the pattern of exposure - once-daily administration stimulates new bone formation, while continuous excess (as in hyperparathyroidism) may be detrimental to the skeleton 1

PTH-Related Disease Conditions

1. Hypoparathyroidism

• Characterized by inadequately low circulating PTH resulting in hypocalcemia and hyperphosphatemia 4
• Most commonly caused by inadvertent damage to parathyroid glands during neck surgery, followed by genetic, idiopathic, and autoimmune etiologies 5, 4
• Clinical manifestations include increased neuromuscular irritability, tingling, muscle cramps, and seizures due to hypocalcemia 4
• Treatment options include:
  • Conventional therapy with oral calcium and active vitamin D supplements 5, 4
  • PTH replacement therapy using recombinant human PTH(1-84), which has been FDA-approved for management of hypoparathyroidism 5, 4

2. Primary Hyperparathyroidism

• Characterized by excessive PTH secretion, typically from a single parathyroid adenoma, resulting in hypercalcemia 6
• Other causes include multiglandular disease and parathyroid cancer 6
• Treatment involves:
  • Parathyroidectomy for all symptomatic patients and many asymptomatic patients 6
  • For patients with normocalcemic primary hyperparathyroidism, accurate measurement of PTH is essential for diagnosis 7

3. Secondary Hyperparathyroidism

• Most commonly caused by chronic kidney disease (CKD) where decreased kidney function leads to phosphate retention, decreased vitamin D activation, and hypocalcemia, stimulating PTH production 3, 8
• Can also result from severe calcium or vitamin D deficiency 6
• In CKD, PTH levels begin to rise when GFR falls below 60 mL/min/1.73 m² 7
• Treatment approaches include:
  • Dietary phosphate restriction when PTH levels are elevated in CKD Stage 3 3
  • Phosphate binders to control serum phosphorus levels 6, 8
  • Vitamin D analogs to suppress PTH production 6, 8
  • Calcimimetics (like cinacalcet) which increase sensitivity of calcium-sensing receptors 7
  • For dialysis patients with serum intact PTH levels >300 pg/mL, active vitamin D sterols are recommended to reduce PTH to 150-300 pg/mL 3

4. Tertiary Hyperparathyroidism

• Occurs when secondary hyperparathyroidism becomes autonomous and parathyroid glands continue to secrete excessive PTH despite normalization of stimulating factors 6, 8
• Most commonly seen in advanced CKD and after kidney transplantation 6
• Treatment is similar to secondary hyperparathyroidism, with parathyroidectomy reserved for severe cases 6

5. Adynamic Bone Disease

• Characterized by low bone turnover associated with low PTH levels 7
• Commonly seen in dialysis patients, aging, and diabetes 7
• Associated with increased risk of fractures and calcification 7
• Treatment may include lowering dialysate calcium concentration (1.5 to 2.0 mEq/L) to stimulate PTH and increase bone turnover 7

Monitoring and Treatment Considerations

• For CKD patients, PTH should be measured when GFR falls below 60 mL/min/1.73 m² 7
• Target ranges for plasma levels of intact PTH vary by CKD stage 7
• For patients treated with vitamin D sterols, serum calcium and phosphorus should be monitored at least every 2 weeks for 1 month and then monthly thereafter 3
• Total elemental calcium intake (dietary plus calcium-based phosphate binders) should not exceed 2,000 mg/day 7
• The serum calcium-phosphorus product should be maintained at <55 mg²/dL² 7
• Different PTH assay generations may yield different results, which can affect clinical decisions, particularly in CKD 7

Therapeutic Applications of PTH

• Recombinant human PTH(1-84) has been approved for the treatment of hypoparathyroidism 5, 4
• Teriparatide (PTH 1-34) stimulates new bone formation and is used in osteoporosis treatment 1
• When administered once daily, teriparatide causes transient increases in serum calcium, peaking 4-6 hours after dosing 1

Complications and Pitfalls

• Conventional treatment of hypoparathyroidism with calcium and vitamin D can lead to hypercalciuria, nephrocalcinosis, kidney stones, and brain calcifications 4
• In CKD, PTH can act as a uremic toxin, contributing to bone loss, soft tissue calcification, cardiomyopathy, immunodeficiency, and muscle weakness 8
• Adynamic bone disease is associated with increased risk of hypercalcemia, metastatic calcification, and calciphylaxis 7
• Accurate measurement of PTH is challenging due to the presence of PTH fragments, which are measured differently by various assay generations 7