Last updated: May 26, 2023

Summarytoggle arrow icon

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.

Drug examplestoggle arrow icon

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

Pharmacodynamicstoggle arrow icon

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.


Adverse effectstoggle arrow icon

  • 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.,:
      • 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.

Indicationstoggle arrow icon

References: [5]

Contraindicationstoggle arrow icon

  • 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
  • Pregnancy/lactation period: no clear contraindications, individual risks/benefits must be weighed

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

Referencestoggle arrow icon

  1. Drake MT, Clarke BL, Khosla S. Bisphosphonates: Mechanism of Action and Role in Clinical Practice. Mayo Clinic Proceedings. 2008; 83 (9): p.1032-1045.doi: 10.4065/83.9.1032 . | Open in Read by QxMD
  2. Russell RGG. Bisphosphonates: Mode of Action and Pharmacology. Pediatrics. 2007; 119 (Supplement 2): p.S150-S162.doi: 10.1542/peds.2006-2023h . | Open in Read by QxMD
  3. Tsoumpra MK, Muniz JR, Barnett BL, et al. The inhibition of human farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates. Elucidating the role of active site threonine 201 and tyrosine 204 residues using enzyme mutants. Bone. 2015; 81: p.478-486.doi: 10.1016/j.bone.2015.08.020 . | Open in Read by QxMD
  4. Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education ; 2014
  5. Rosen HN. Pharmacology of bisphosphonates. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated: June 8, 2015. Accessed: February 21, 2017.
  6. Bisphosphonates. . Accessed: February 21, 2017.
  7. Reid IR. Bisphosphonates: New Indications and Methods of Administration. Curr Opin Rheumatol. 2003; 15 (4).
  8. Graham R, Russel G. Bisphosphonates: Mode of Action and Pharmacology. Pediatrics. 2007; 119 (2).
  9. Greenspan SL , Harris ST, Bone H et al. Bisphosphonates: Safety and Efficacy in the Treatment and Prevention of Osteoporosis. Am Fam Physician. 2000; 1 (61): p.2731-2736.
  10. Walton RJ, Russell RG, Smith R. Changes in the renal and extrarenal handling of phosphate induced by disodium etidronate (EHDP) in man.. Clin Sci Mol Med. 1975; 49 (1): p.45-56.doi: 10.1042/cs0490045 . | Open in Read by QxMD
  11. Rosen HN. Risks of bisphosphonate therapy in patients with osteoporosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Last updated: January 6, 2016. Accessed: February 21, 2017.
  12. Rosella D, Papi P, Giardino R, Cicalini E, Piccoli L, Pompa G. Medication-related osteonecrosis of the jaw: Clinical and practical guidelines. J Int Soc Prev Community Dent. 2016; 6 (2): p.97–104.doi: 10.4103/2231-0762.178742 . | Open in Read by QxMD
  13. Osteonecrosis of the Jaw. Updated: September 1, 2013. Accessed: February 21, 2017.
  14. Liamis G, Milionis HJ, Elisaf M. Medication-induced hypophosphatemia: a review. QJM. 2010; 103 (7): p.449-459.doi: 10.1093/qjmed/hcq039 . | Open in Read by QxMD
  15. Jeremiah MP, Unwin BK, Greenawald MH, Casiano VE. Diagnosis and Management of Osteoporosis. Am Fam Physician. 2015; 92 (4): p.261-8.

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