Drugs Affecting Calcium Metabolism

Calcium Regulation Overview - Hormone Harmony

• Normal serum Ca²⁺: 8.5-10.5 mg/dL. Maintained by PTH, Vitamin D, Calcitonin.
• PTH (Parathyroid Hormone): Primary hypercalcemic. ↑ Serum Ca²⁺, ↓ PO₄³⁻.
  • Bone: Stimulates osteoclasts → ↑ Ca²⁺ resorption.
  • Kidney: ↑ Ca²⁺ reabsorption, ↓ PO₄³⁻ reabsorption, activates Vit D ($1\alpha$-hydroxylase).
  • 📌 PTH: Phosphate Trashing Hormone.
• Vitamin D (Calcitriol, $1,25(OH)_2D_3$): Steroid. ↑ Serum Ca²⁺ & PO₄³⁻.
  • Intestine: Major site for ↑ Ca²⁺ & PO₄³⁻ absorption.
  • Bone: For mineralization; high doses ↑ resorption.
• Calcitonin: From thyroid C-cells. ↓ Serum Ca²⁺ (minor role).
  • Bone: Inhibits osteoclasts → ↓ Ca²⁺ resorption.

⭐ Primary hyperparathyroidism is a major cause of hypercalcemia, classically presenting with "stones, bones, abdominal groans, and psychic moans".

Hypercalcemic Agents - Calcium Crusaders

• Calcium Supplements: Used for hypocalcemia, osteoporosis.
  • Oral:
    • Calcium Carbonate: Most common, requires acid (take with meals). 📌 "Carbonate needs Carbs (food)".
    • Calcium Citrate: Better absorption, acid-independent.
  • IV:
    • Calcium Gluconate: Preferred for IV.
    • Calcium Chloride: More irritating, higher $Ca^{2+}$ content.
• Vitamin D & Analogs: ↑ $Ca^{2+}$ absorption.
  • Mechanism: ↑ intestinal $Ca^{2+}$ & $PO_4^{3-}$ absorption, modulates bone turnover, ↓ renal $Ca^{2+}$ excretion (via PTH).
  • Forms:
    • Cholecalciferol ($D_3$), Ergocalciferol ($D_2$): Prodrugs, need liver & kidney activation.
    • Calcifediol ($25-OH D_3$): Needs kidney activation.
    • Calcitriol ($1,25-(OH)_2 D_3$): Active form; for renal failure.
    • Analogs (e.g., Paricalcitol): For secondary hyperparathyroidism in CKD.
  • Uses: Osteomalacia, rickets, hypoparathyroidism, osteoporosis.
  • Toxicity: Hypercalcemia, hypercalciuria.
• Teriparatide (PTH Analog): Recombinant PTH (1-34).
  • Mechanism: Intermittent SC admin → ↑ osteoblast activity > osteoclast activity (anabolic effect).
  • Uses: Severe osteoporosis (postmenopausal, steroid-induced).
  • Duration: Max 2 years (risk of osteosarcoma in animal studies).

  ⭐ Teriparatide is the only osteoporosis drug that primarily stimulates new bone formation.

Hypocalcemic Agents & Bone Anti-resorptives - Calcium Calmers

• Bisphosphonates: Pyrophosphate analogs; inhibit osteoclast resorption.

  • Types:
    • Non-Nitrogen (e.g., Etidronate): Less potent.
    • Nitrogen-containing (e.g., Alendronate, Zoledronate): More potent.
  • Oral Admin: Empty stomach, water, upright 30-60 min (prevents esophagitis). 📌 "DRONATE" to bone, don't irritate esophagus.
  • Uses: Osteoporosis, Paget's, malignant hypercalcemia.
  • AEs: Esophagitis, ONJ, atypical fractures, hypocalcemia, acute phase reaction (IV).

  ⭐ Oral bisphosphonates (e.g., Alendronate) must be taken with a full glass of water, on an empty stomach, and the patient must remain upright for at least 30 minutes to prevent esophageal irritation and ulceration.

• Calcitonin (Salmon): Inhibits osteoclasts; ↑ renal Ca²⁺ excretion.

  • Uses: Acute hypercalcemia (rapid, short-lived), Paget's, osteoporosis (nasal; less fracture benefit).
  • AEs: Nausea, flushing, rhinitis, tachyphylaxis.

• Denosumab: MAb vs RANKL; ↓ osteoclast formation, function, survival.

  • Admin: SC q 6 months.
  • Uses: Osteoporosis (high-risk), drug-induced bone loss, bone metastases.
  • AEs: Hypocalcemia, ONJ, atypical fractures, infections, skin reactions.

• Cinacalcet: Calcimimetic; allosterically activates CaSR on parathyroid gland → ↓ PTH.

  • Uses: 2° Hyperparathyroidism (CKD), Parathyroid Ca (hypercalcemia).
  • AEs: Hypocalcemia, nausea.

• Others (Specialized):

  • Gallium Nitrate: IV for malignant hypercalcemia. Nephrotoxic.
  • Plicamycin (Mithramycin): Cytotoxic Abx; inhibits osteoclast RNA synthesis. For severe refractory hypercalcemia. Highly toxic.

High‑Yield Points - ⚡ Biggest Takeaways

• Bisphosphonates: Inhibit osteoclasts; for osteoporosis. Risks: esophagitis, ONJ.
• Teriparatide: PTH analog, anabolic (stimulates osteoblasts); for severe osteoporosis.
• Denosumab: Anti-RANKL mAb, blocks osteoclast maturation; for postmenopausal osteoporosis.
• Calcitonin: Inhibits osteoclasts; for Paget's disease, acute hypercalcemia.
• Vitamin D: ↑ Ca²⁺ absorption; for rickets, osteomalacia, hypoparathyroidism.
• Cinacalcet: Calcimimetic, ↓PTH; for secondary hyperparathyroidism (CKD), parathyroid Ca.
• Raloxifene: SERM, bone-protective estrogenic effect; for postmenopausal osteoporosis.