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. However, nitrogen-containing bisphosphonates work by a different molecular pathway than simple bisphosphonates and have a stronger effect. 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.

• Bisphosphonates 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
  • 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
• Also inhibit mineralization
• Additionally: prevention of osteoblast apoptosis and inhibition of osteocyte apoptosis

The nitrogen-containing bisphosphonates have a stronger effect than the simple bisphosphonates!

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]}

• General
  • Hypocalcemia and hypophosphatemia (hypocalcemia can also lead to osteomalacia, see osteomalacia and rickets)
  • Aseptic osteonecrosis of the jaw: mostly in high-dose IV administration in tumor patients, but can also occur with oral administration and in other patients
  • Atypical fractures (particularly of the femur)
  • Musculoskeletal pain
  • Atrial fibrillation
  • Renal impairment
  • Ocular inflammation and visual disturbances
• Oral bisphosphonates; (alendronate, risedronate, etidronate, tiludronate): esophageal inflammation and cancer
• 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:^{[2][7][8][9][10]}

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

• Osteoporosis
• Hypercalcemia
• Tumor-induced osteolysis
• Multiple myeloma
• Paget's disease of bone
• Hereditary skeletal disorders

References:^[2]