Chemistry and Pharmacodynamics
Chemical structure
Structure of bisphosphonate:
The basic structure of bisphosphonate is centered around a common phosphorus-carbon-phosphorus bond, but the R groups may vary.
- 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
Pharmacokinetics
Absorption
- Absorbed in the GI tract through paracellular transport
- In general, poorly absorbed in the GI tract
Distribution
- Binds bone
- Preferentially binds to regions of bone with a high rate of turnover
Metabolism
- Not metabolized
- Long half-life (may exceed 10 years)
Excretion
- Half excreted unchanged by the kidney
- Half absorbed on the bone surface
Classification
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
Indications
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)
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.
Warnings
- 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.
Contraindications
- 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
| Medication | Classification | Half-life elimination | Indication |
|---|---|---|---|
| Alendronate | Nitrogenous | > 10 years |
|
| Risedronate | 480–561 hours (terminal) | ||
| Pamidronate | Approximately 28 hours | In addition to the above:
| |
| Zoledronic acid | 146 hours (terminal) | ||
| Etidronate | Nonnitrogenous | 1–6 hours |
|
| Clodronate | 13 hours (terminal) |
| |
| Tiludronate | 40–60 hours |
References
- 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.
