Bisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix “-dronate” or “-dronic acid” (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption. Bisphosphonates are indicated for postmenopausal osteoporosis, glucocorticoid-induced osteopenia/osteoporosis, and Paget disease of the bone. Adverse effects include hypocalcemia, hypophosphatemia, avascular necrosis of the femur, and osteonecrosis of the jaw. Contraindications include hypersensitivity reactions and esophageal disorders. Bisphosphonates may interact with aminoglycosides, aspirin, and proton pump inhibitors.

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Chemistry and Pharmacodynamics

Chemical structure

Structure of bisphosphonate

Structure of bisphosphonate:
The basic structure of bisphosphonate is centered around a common phosphorus-carbon-phosphorus bond, but the R groups may vary.

Image: “Structure of bisphosphonate” by Jü. License: Public Domain
  • Pyrophosphate analogs, which mimic the structure of pyrophosphate
  • Common phosphorus-carbon-phosphorus chain
  • Long chain: R2 side chain determines the drug strength
  • Short chain: R1 side chain determines the pharmacokinetics

Mechanism of action

  1. Bisphosphonates bind to hydroxyapatite crystals in the bone matrix.
  2. Osteoclasts bind to and phagocytose bisphosphonate:
    • Nitrogen-containing bisphosphonates inhibit farnesyl pyrophosphate synthetase → promote detachment of the osteoclast from the bone
    • Simple bisphosphonates are metabolized to metabolites, which prevent ATP use → apoptosis
  3. ↓ Osteoclast-mediated bone resorption
  4. Indirectly increase bone formation and bone mineral density



  • Absorbed in the GI tract through paracellular transport
  • In general, poorly absorbed in the GI tract


  • Binds bone
  • Preferentially binds to regions of bone with a high rate of turnover


  • Not metabolized
  • Long half-life (may exceed 10 years)


  • Half excreted unchanged by the kidney
  • Half absorbed on the bone surface


Bisphosphonates are classified by structure. Bisphosphonate compounds are either nitrogenous or nonnitrogenous. The nitrogenous subtype contains nitrogen in the long chain (R2).

  • Nitrogenous (more potent osteoclast inhibitors):
    • Pamidronate
    • Alendronate
    • Risedronate
    • Zoledronic acid
  • Nonnitrogenous (simple):
    • Etidronate
    • Clodronate
    • Tiludronate


Bisphosphonates treat a number of conditions associated with bones:

  • Postmenopausal osteoporosis:
    • 1st-line therapy
    • Increases bone mineral density
  • Prevention of osteoporosis related to:
    • Glucocorticoids
    • Androgen deprivation therapy
  • Paget disease of the bone (osteitis deformans):
    • 1st-line therapy
    • Inhibits initial osteoclast overactivation
  • Bone metastases:
    • Reduces the risk of skeletal-related events
    • Zoledronic acid is preferred. 
  • Hypercalcemia of malignancy: reduces bone resorption due to parathyroid-related peptide or bone metastasis
  • Hyperparathyroidism: improves bone density
  • Osteogenesis imperfecta (off label)
Osteoporosis of spine

Diagram of pathological changes seen in a vertebral column with osteoporosis:
The gradual loss of bone density makes the vertebrae collapse, resulting in kyphosis.

Image: “Osteoporosis of Spine” by OpenStax College. License: CC BY 3.0

Adverse Effects and Contraindications

Adverse effects

  • Common:
    • Hypocalcemia due to decreased calcium release from bone
    • Hypophosphatemia due to decreased phosphate release from bone
    • Pill-induced esophagitis
    • Diarrhea
    • Constipation
    • Flatulence
  • Rare:
    • Headache
    • Muscle cramps
  • Very rare:
    • Dysgeusia
    • Alopecia
    • Peripheral edema
    • Avascular necrosis of the femur
    • Osteonecrosis of the jaw

A radiograph of avascular necrosis showing osteopenia, sclerosis, and rim calcification:
The classic sign of advanced disease is a crescent shape caused by subchondral bone accumulation and collapse of the articular surface.

Image: “X-ray of idiopathic avascular necrosis of the femoral head – Lateral” by Mikael Häggström, M.D. License: CC0 1.0


  • Severe bone, muscle, or joint pain
  • Use caution in patients with renal disease.
  • Avoid in patients following bariatric surgery due to the risk of ulceration and poor absorption.


  • Hypersensitivity reactions
  • Hypocalcemia
  • Esophageal disorders with delayed esophageal emptying:
    • Achalasia
    • Stricture
  • Inability to stand or sit upright for at least 30 minutes

Drug interactions

  • Aminoglycosides: exacerbate bisphosphonate-induced hypocalcemia
  • Aspirin: increase upper GI side effects of alendronate
  • Proton pump inhibitors: decrease bisphosphonate absorption

Comparison of Bisphosphonate Medications

Table: Comparison of medications within the bisphosphonate class
MedicationClassificationHalf-life eliminationIndication
AlendronateNitrogenous> 10 years
  • Osteoporosis
  • Paget disease
Risedronate480–561 hours (terminal)
PamidronateApproximately 28 hoursIn addition to the above:
  • Bone metastasis
  • Hypercalcemia of malignancy
  • Osteolytic lesions
  • Hyperparathyroidism
Zoledronic acid146 hours (terminal)
EtidronateNonnitrogenous1–6 hours
  • Paget disease
  • Heterotopic ossification
Clodronate13 hours (terminal)
  • Hypercalcemia of malignancy
  • Bone metastasis
  • Paget disease
Tiludronate40–60 hours


  1. Rosen, H.R. (2020). Risks of bisphosphonate therapy in patients with osteoporosis. UpToDate. Retrieved June 11, 2021, from
  2. Rosen, H.R. (2021). Pharmacology of bisphosphonates. UpToDate. Retrieved June 11, 2021, from
  3. Charles, J.F. (2020). Treatment of Paget disease of bone. UpToDate. Retrieved June 11, 2021, from
  4. Drake, M.T., Clarke, B.L., Khosla, S. (2008). Bisphosphonates: Mechanism of action and role in clinical practice. Mayo Clin Proc. PMID: 18775204. Retrieved June 11, 2021, from
  5. Bikle, D.D. (2012). Agents that affect bone mineral homeostasis. Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic & Clinical Pharmacology (12th edition, pp. 776). McGraw Hill.

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