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Pharmacology Notes: Hormones Regulating Calcium

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Overview of Calcium Homeostasis

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1. PARATHYROID HORMONE (PTH)

Structure & Secretion

• 84-amino acid peptide; biologically active fragment = PTH(1-34)
• Secreted by chief cells of parathyroid glands
• Regulated by Calcium-Sensing Receptor (CaSR) - a GPCR on parathyroid cells
  • ↓ Ca²⁺ → CaSR inhibited → ↑ PTH secretion
  • ↑ Ca²⁺ → CaSR activated (via phospholipase C / IP3 / DAG) → ↓ PTH secretion
  • Even a small drop in Ca²⁺ can double or triple plasma PTH; chronic deficiency causes gland hypertrophy up to 5-fold

Mechanism of Action (3 target organs)

• Rapid phase (minutes-hours): Activates osteocyte/osteoblast membrane pump (osteolysis) - releases Ca²⁺ from bone fluid to ECF without matrix resorption
• Slow phase (days-weeks): Stimulates osteoclast proliferation → increased osteoclastic bone resorption (raises both Ca²⁺ and PO₄³⁻)

• ↑ Ca²⁺ reabsorption (distal tubule)
• ↓ Phosphate reabsorption (proximal tubule) → phosphaturia
• ↑ 1α-hydroxylase activity → converts 25-OH-D₃ to 1,25-(OH)₂D₃ (calcitriol)

• ↑ Ca²⁺ and PO₄³⁻ absorption

Net effect: ↑ plasma Ca²⁺, ↓ plasma PO₄³⁻

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2. VITAMIN D

Synthesis Pathway (exam favourite)

Skin: 7-dehydrocholesterol → UV light → Cholecalciferol (Vit D3)
     Diet: Ergocalciferol (Vit D2)
          ↓ 25-hydroxylase (liver)
     25-hydroxycholecalciferol [storage form, t½ ~3 weeks]
          ↓ 1α-hydroxylase (kidney) ← stimulated by PTH, hypophosphatemia
     1,25-(OH)₂D₃ = CALCITRIOL [active form]

Mechanism of Action

• Nuclear receptor (VDR) - genomic action
• Intestine: ↑ calbindin synthesis → ↑ Ca²⁺ and PO₄³⁻ absorption (main action)
• Bone: ↑ bone mineralization; large doses cause bone resorption
• Kidney: ↑ Ca²⁺ and PO₄³⁻ reabsorption (minor effect)
• Parathyroid: ↓ PTH gene transcription (negative feedback)
• Immune modulation: ↓ cytokine production, autoimmune protection

Vitamin D Preparations (Exam-Ready Table)

Deficiency States

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3. CALCITONIN

Structure & Secretion

• 32-amino acid peptide, MW ~3,400 Da
• Secreted by parafollicular C cells of thyroid (only ~0.1% of gland mass)
• Stimulus: ↑ Ca²⁺ → ↑ calcitonin (opposite of PTH)
• Receptor: CTR - a GPCR coupling to multiple G proteins

Actions

1. Inhibits osteoclast activity (main mechanism) → reduces bone resorption → ↓ Ca²⁺ and PO₄³⁻
2. Promotes calcium deposition in bone
3. Minor renal effects: ↓ Ca²⁺ and PO₄³⁻ reabsorption (opposite to PTH)

Clinical reality: WEAK effect in adult humans

• Any initial Ca²⁺ drop triggers compensatory ↑ PTH, which overrides calcitonin
• Calcitonin effect is mainly transient (hours to a few days)
• Much more important in young animals and children than in adults

Therapeutic Uses

• Hypercalcemia (short-term; injection or nasal spray)
• Paget disease (second-line)
• Postmenopausal osteoporosis (nasal spray; largely replaced by bisphosphonates)
• Diagnosis of medullary thyroid carcinoma (MTC) - calcitonin is a sensitive/specific tumour marker for MTC

Adverse Effects

• Nausea, facial flushing, local reactions at injection site
• Tachyphylaxis (reduced response on repeated dosing)

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4. DRUGS TARGETING CALCIUM HOMEOSTASIS

A. PTH Analogues (Anabolic Agents)

B. Calcimimetics (CaSR Agonists)

C. Bisphosphonates (Anti-Resorptive)

• Oral bioavailability very poor (<1-6%)
• Reduced further by food, Ca²⁺ supplements, antacids with divalent cations
• Take on empty stomach, with full glass of water, remain upright ≥30 min
• Renally excreted; avoid if CrCl <30 mL/min
• Distributes into bone (long t½)

• Oral: esophagitis, heartburn, abdominal pain (contraindicated in active upper GI disease)
• Osteonecrosis of the jaw (ONJ) - rare (~2/100,000 patient-years)
• Atypical femoral shaft fractures (especially alendronate, zoledronate)
• Zoledronate: severe hypocalcemia, nephrotoxicity (infuse over ≥15 min)
• Flu-like symptoms with IV infusion (pamidronate, zoledronate) - transient

D. RANKL Inhibitor

E. FGF23

• Secreted by osteocytes in response to ↑ phosphate load and ↑ 1,25-(OH)₂D₃
• Promotes urinary phosphate excretion; suppresses 1α-hydroxylase (↓ calcitriol)
• Unlike PTH, also suppresses intestinal phosphate absorption
• Requires α-klotho as co-receptor for FGFR signalling

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5. DISORDERS - QUICK PHARMACOLOGY SUMMARY

Hypocalcemia / Hypoparathyroidism

• Acute: IV calcium gluconate (tetany emergency)
• Chronic: Oral calcium + activated vitamin D (calcitriol) ± alfacalcidol
• Hypoparathyroidism: Large doses of vitamin D + 1-2 g oral calcium; consider 1,25-(OH)₂D₃ for faster action

Hypercalcemia

1. IV hydration + furosemide (increase renal Ca²⁺ excretion)
2. Bisphosphonates - pamidronate IV or zoledronate IV (drug of choice for hypercalcemia of malignancy)
3. Calcitonin - rapid but short-lived effect; useful as bridge
4. Glucocorticoids - in vitamin D toxicity, granulomatous disease, lymphoma
5. Cinacalcet - for primary/secondary hyperparathyroidism

Osteoporosis

• First-line: Bisphosphonates (alendronate, risedronate, zoledronate)
• Anabolic: Teriparatide or abaloparatide (severe OP, fractures)
• Hormone therapy: Estrogens, SERMs (raloxifene)
• Anti-RANKL: Denosumab

Secondary Hyperparathyroidism (CKD)

• Active vitamin D analogues: Calcitriol, paricalcitol
• Calcimimetic: Cinacalcet (oral) or Etelcalcetide (IV)
• Phosphate binders: calcium carbonate, sevelamer

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6. HIGH-YIELD EXAM MNEMONICS

• Bone resorption ↑
• Intestinal Ca²⁺ absorption ↑ (via calcitriol)
• Kidney: Ca²⁺ ↑, PO₄³⁻ ↓
• Enzyme 1α-hydroxylase ↑ (activates vit D)

• Calcitonin = "C" for Cold (inhibits osteoclasts, lowers Ca²⁺)
• PTH = parathyroid = raises Ca²⁺

• Empty stomach + water + upright = no esophagitis
• No use if CrCl <30 mL/min

• Skin → Liver (25-OH) → Kidney (1α-OH) = active calcitriol
• PTH stimulates the kidney step; FGF23 inhibits it

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