Bisphosphonates

Bisphosphonates (e.g., etidronate, alendronate) are used for the treatment of hypercalcemia and bone metabolism disorders, such as osteoporosis or tumor-induced osteolysis. All bisphosphonates primarily slow down the degradation of bone substance by interfering with osteoclast function. Important side effects of bisphosphonate therapy include hypocalcemia, renal impairment, and aseptic osteonecrosis of the jaw. Therefore, bisphosphonates are contraindicated in patients with hypocalcemia and those with a limited glomerular filtration rate (GFR). Additionally, oral bisphosphonates may cause esophageal damage while IV bisphosphonates can induce flu-like symptoms.

• Alendronate
• Risedronate
• Ibandronate
• Zoledronate
• Etidronate
• Tiludronate
• Pamidronate

• Bisphosphonates are pyrophosphate analogs that bind to hydroxyapatite binding sites on the surface of bone tissue: uptake by osteoclasts during phases of bone resorption → interference with osteoclast function and promotion of osteoclast apoptosis → reduced bone resorption
  • Simple bisphosphonates (tiludronate, etidronate) : reduction of osteoclast proton production, suppression of osteoclast maturation and recruitment, and promotion of osteoclast apoptosis ^[1]
  • Nitrogen-containing bisphosphonates (alendronate, risedronate, zoledronate): inhibition of the enzyme farnesyl pyrophosphate synthase → disturbance of osteoclast metabolism and signaling → reduced osteoclast function and promotion of osteoclast apoptosis ^[2][3]
• Inhibit mineralization (structurally similar to pyrophosphate, a natural inhibitor of bone mineralization)

The nitrogen-containing bisphosphonates have a stronger effect than the simple bisphosphonates! ^[2]

Bisphosphonates also reduce bone formation since bone resorption and formation are intrinsically connected. However, bone resorption is reduced more severely than bone formation.

References:^{[1][2][3][4][5][6][7][8][9]}

• General
  • Hypocalcemia; (usually mild, but may lead to osteomalacia; see “Osteomalacia and rickets”) and hypophosphatemia (usually transient and mild; hyperphosphatemia has also been reported) ^[10]
  • Bisphosphonate-related osteonecrosis of the jaw: adverse effect of bisphosphonates, usually seen with high-dose IV administration in tumor patients
    • Etiology: Trauma to the jaw (e.g., tooth extractions or other dental procedures) is a trigger in many cases.
    • Pathophysiology: not yet fully understood
    • Clinical features: chronic swelling, mild pain, exposed necrotic bone
    • Treatment: supportive, e.g.,:
      • Improving oral hygiene
      • Antibiotic rinses
      • Limited debridement
    • Prevention
      • Dental examination in conjunction with treatment of preexisting dental conditions (e.g., extraction of unrestorable teeth) prior to initiation of therapy
      • Establishing a daily oral care plan that involves daily oral rinsing, brushing, and flossing
  • Atypical femoral fractures
  • Musculoskeletal pain
  • Atrial fibrillation
  • Renal impairment
  • Ocular inflammation and visual disturbances
• Oral bisphosphonates (alendronate, risedronate, etidronate, tiludronate)
  • Esophageal inflammation and cancer
  • To avoid this complication, patients should swallow medication with a sufficient amount of water and maintain an upright position for 30 minutes.
• IV bisphosphonates (zolendronate); : acute-phase reaction with flulike symptoms; (e.g., fever, joint, and muscle pain) 24–72 hours after administration

Bisphosphonates should be taken in the morning with sufficient water and in an upright position at least 60 minutes before eating!

References: ^{[5][11][12][13][14]}

We list the most important adverse effects. The selection is not exhaustive.

• Osteoporosis
• Hypercalcemia
• Tumor-induced osteolysis (e.g., metastasis to the bone)
• Multiple myeloma
• Paget's disease of bone
• Hereditary skeletal disorders (e.g., osteogenesis imperfecta)

References: ^[5]

• Common to all bisphosphonates
  • Hypersensitivity
  • Esophageal abnormalities (e.g., strictures)
  • Inability to stand or sit upright for at least 30 minutes after oral bisphosphonate therapy
• For zoledronic acid
  • Hypocalcemia
  • Reduced creatinine clearance (< 30–35 ml/min/1.73 m2)
• Pregnancy/lactation period: no clear contraindications, individual risks/benefits must be weighed

We list the most important contraindications. The selection is not exhaustive.