How is serum calcium regulated and what body system dysfunctions cause calcium abnormalities like hypercalcemia or hypocalcemia?

Serum Calcium Regulation and Disorders

Serum calcium is tightly regulated by parathyroid hormone (PTH), vitamin D, and fibroblast growth factor 23 (FGF23), which act on four primary target organs: bone, kidney, intestine, and parathyroid glands. 1

Physiological Regulation of Serum Calcium

Key Hormones and Their Functions

1. Parathyroid Hormone (PTH)

   • Released in response to hypocalcemia detected by calcium-sensing receptors on parathyroid glands 1
   • Increases serum calcium through three mechanisms:
     • Stimulates 1-α-hydroxylase (CYP27B1) to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D
     • Increases calcium reabsorption and decreases phosphate reabsorption in renal tubules
     • Promotes calcium and phosphate release from bone 1

2. Vitamin D (1,25-dihydroxyvitamin D)

   • Activated form increases intestinal calcium absorption
   • Works synergistically with PTH to maintain calcium homeostasis 1, 2

3. Fibroblast Growth Factor 23 (FGF23)

   • Secreted by osteocytes and osteoblasts
   • Increases phosphate excretion
   • Inhibits CYP27B1, decreasing 1,25-dihydroxyvitamin D levels
   • Suppresses PTH secretion 1

4. Calcitonin

   • Released in response to hypercalcemia
   • Inhibits bone resorption
   • Decreases serum calcium levels 3

Regulatory Feedback Loops

• Hypocalcemia → PTH release → increased calcium reabsorption, bone resorption, and vitamin D activation → increased serum calcium
• Hypercalcemia → decreased PTH release → decreased calcium reabsorption and vitamin D activation → decreased serum calcium 1

Body System Dysfunctions Causing Calcium Abnormalities

Causes of Hypercalcemia

1. Parathyroid Disorders

   • Primary hyperparathyroidism (accounts for ~90% of hypercalcemia cases along with malignancy) 4
   • Parathyroid carcinoma 5

2. Malignancy

   • Osteolytic metastases
   • Humoral hypercalcemia of malignancy (PTH-related protein secretion)
   • Multiple myeloma 4, 6

3. Kidney Dysfunction

   • Tertiary hyperparathyroidism in advanced CKD
   • Decreased calcium excretion 1

4. Endocrine Disorders

   • Thyroid disorders
   • Adrenal insufficiency 4

5. Medication/Supplement-Induced

   • Vitamin D intoxication
   • Thiazide diuretics
   • Calcium supplements
   • Lithium
   • Vitamin A excess 4

6. Other Causes

   • Granulomatous diseases (sarcoidosis, tuberculosis)
   • Immobilization
   • Milk-alkali syndrome 4, 6

Causes of Hypocalcemia

1. Parathyroid Disorders

   • Hypoparathyroidism (75% surgical, 25% primary) 6
   • Pseudohypoparathyroidism (PTH resistance)

2. Vitamin D Disorders

   • Vitamin D deficiency
   • Vitamin D resistance
   • Impaired vitamin D metabolism (CKD) 2, 7

3. Kidney Dysfunction

   • Chronic kidney disease (impaired vitamin D activation)
   • Acute kidney injury with hyperphosphatemia 1

4. Medication-Induced

   • Bisphosphonates
   • Denosumab
   • Cinacalcet 5
   • Anticonvulsants 7

5. Other Causes

   • Magnesium deficiency (impairs PTH secretion and action) 7
   • Acute pancreatitis
   • Tumor lysis syndrome
   • Hungry bone syndrome post-parathyroidectomy 2, 7

Clinical Implications and Management

Monitoring Calcium Levels

• Serum calcium should be measured at least every 3 months in CKD patients 2
• Corrected calcium formula: Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)] 2
• Target calcium levels in CKD: 8.4-9.5 mg/dL (2.1-2.37 mmol/L) 2

Management of Hypercalcemia

• Mild hypercalcemia (total calcium <12 mg/dL): Often asymptomatic, may require observation 4
• Severe hypercalcemia (total calcium ≥14 mg/dL):
  • Hydration with intravenous fluids
  • Bisphosphonates (zoledronic acid or pamidronate)
  • For patients with kidney failure: denosumab and dialysis
  • Glucocorticoids for vitamin D intoxication or granulomatous disorders 4, 6

Management of Hypocalcemia

• Severe symptomatic hypocalcemia:

  • Calcium gluconate infusion (1-2 mg elemental calcium/kg/hr)
  • Transition to oral calcium carbonate (1-2g three times daily)
  • Add calcitriol (up to 2 μg/day) when oral intake is possible 2

• Chronic hypocalcemia:

  • Oral calcium supplements
  • Vitamin D supplementation (if 25-hydroxyvitamin D <30 ng/mL) 2
  • Monitor magnesium levels and correct deficiency 2, 7

Special Considerations

• CKD patients:

  • Target iPTH levels in CKD stage 5 (dialysis): 150-300 pg/mL 1, 2
  • Cinacalcet is indicated for secondary hyperparathyroidism in CKD patients on dialysis, but contraindicated in those not on dialysis due to hypocalcemia risk 5
  • Phosphate management is crucial (target: 3.5-5.5 mg/dL in CKD stage 5) 1, 2

• Medication-related considerations:

  • Discontinue cinacalcet if serum calcium falls below 7.5 mg/dL 5
  • When switching from etelcalcetide to cinacalcet, wait at least 4 weeks and ensure normal calcium levels 5
  • Maximum daily elemental calcium from phosphate binders should not exceed 1500 mg 2

Common Pitfalls and Caveats

• Ionized vs. Total Calcium: Acidosis increases ionized calcium despite normal total calcium levels 2
• PTH Assay Variability: Different PTH assays measure different fragments, affecting clinical interpretation 1
• Vitamin D Toxicity: High-dose vitamin D (>4,000 IU/day) has been associated with increased falls and fractures 2
• Calcium-Phosphate Product: Should not exceed 70 mg²/dL² to prevent soft tissue calcification 8
• Magnesium's Role: Magnesium deficiency can cause refractory hypocalcemia by impairing PTH secretion and action 7

Understanding these regulatory mechanisms and potential dysfunctions is essential for proper diagnosis and management of calcium disorders in clinical practice.