Chemistry and Pharmacodynamics
- 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
- Bisphosphonates bind to hydroxyapatite crystals in the bone matrix.
- 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
- ↓ Osteoclast-mediated bone resorption
- 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):
- Zoledronic acid
- Nonnitrogenous (simple):
Bisphosphonates treat a number of conditions associated with bones:
- Postmenopausal osteoporosis:
- 1st-line therapy
- Increases bone mineral density
- Prevention of osteoporosis related to:
- 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)
Adverse Effects and Contraindications
- Hypocalcemia due to decreased calcium release from bone
- Hypophosphatemia due to decreased phosphate release from bone
- Pill-induced esophagitis
- Muscle cramps
- Very rare:
- Peripheral edema
- Avascular necrosis of the femur
- Osteonecrosis of the jaw
- 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
- Esophageal disorders with delayed esophageal emptying:
- Inability to stand or sit upright for at least 30 minutes
- Aminoglycosides: exacerbate bisphosphonate-induced hypocalcemia
- Aspirin: increase upper GI side effects of alendronate
- Proton pump inhibitors: decrease bisphosphonate absorption
Comparison of Bisphosphonate Medications
|Alendronate||Nitrogenous||> 10 years|
|Risedronate||480–561 hours (terminal)|
|Pamidronate||Approximately 28 hours||In addition to the above:|
|Zoledronic acid||146 hours (terminal)|
|Clodronate||13 hours (terminal)|
- Rosen, H.R. (2020). Risks of bisphosphonate therapy in patients with osteoporosis. UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/risks-of-bisphosphonate-therapy-in-patients-with-osteoporosis.
- Rosen, H.R. (2021). Pharmacology of bisphosphonates. UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/pharmacology-of-bisphosphonates?search=bisphosphonates.
- Charles, J.F. (2020). Treatment of Paget disease of bone. UpToDate. Retrieved June 11, 2021, from https://www.uptodate.com/contents/treatment-of-paget-disease-of-bone.
- 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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/.
- 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.