Bisphosphonates

Bisphosphonates are a well-established class of antiresorptive agents that play a central role in the treatment and prevention of metabolic bone diseases characterized by increased bone turnover and bone fragility. They are synthetic analogs of pyrophosphate, a natural regulator of bone mineralization, and are among the most prescribed medications for osteoporosis, Paget’s disease of bone, bone metastases, and hypercalcemia of malignancy.

---

1. Chemical Structure and Classification

Bisphosphonates share a core structure comprising two phosphonate (–PO₃H₂) groups attached to a central carbon atom, forming a P-C-P backbone. This structure allows them to strongly bind to hydroxyapatite crystals in bone, particularly at sites of active bone resorption.

They are classified into two main generations based on their side chains and potency:

Non-Nitrogen-Containing Bisphosphonates (First Generation):

• Etidronate

• Clodronate

• Tiludronate

Nitrogen-Containing Bisphosphonates (Second and Third Generation):

• Alendronate

• Risedronate

• Ibandronate

• Pamidronate

• Zoledronic acid

The presence of a nitrogen-containing side chain increases potency by targeting intracellular enzymes critical for osteoclast function.

---

2. Mechanism of Action

Bisphosphonates inhibit bone resorption by affecting osteoclast activity in two key ways, depending on their chemical subclass:

A. Non-Nitrogen Bisphosphonates:

• Incorporated into ATP analogs that are cytotoxic to osteoclasts

• Cause osteoclast apoptosis via disruption of mitochondrial function

B. Nitrogen Bisphosphonates:

• Inhibit farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway

• Prevent prenylation of small GTP-binding proteins (e.g., Rho, Rac, Ras)

• Disrupt osteoclast cytoskeleton, adhesion, and ruffled border formation

• Induce apoptosis of osteoclasts, suppressing bone resorption

---

3. Approved Bisphosphonate Agents

Oral Agents:

1. Alendronate – Fosamax

   • Daily or weekly dosing

   • Prevention and treatment of osteoporosis

2. Risedronate – Actonel

   • Daily, weekly, or monthly dosing

   • Postmenopausal osteoporosis, glucocorticoid-induced osteoporosis

3. Ibandronate – Boniva

   • Monthly oral or quarterly IV

   • Postmenopausal osteoporosis

4. Etidronate – Didronel

   • Obsolete in many guidelines

   • Formerly used for Paget’s disease

Intravenous Agents:

1. Zoledronic Acid – Reclast (osteoporosis), Zometa (oncology)

   • Once-yearly IV for osteoporosis

   • Monthly or less frequent for malignancy-related bone disease

2. Pamidronate – Aredia

   • IV infusion for hypercalcemia of malignancy, bone metastases

---

4. Clinical Indications

A. Osteoporosis (Postmenopausal, Male, Glucocorticoid-Induced)

• First-line therapy for reducing the risk of:

  • Vertebral fractures

  • Non-vertebral fractures

  • Hip fractures

B. Paget’s Disease of Bone

• Normalize alkaline phosphatase levels

• Reduce bone pain

• Improve bone architecture

C. Oncology Indications

• Reduce skeletal-related events in:

  • Breast cancer with bone metastasis

  • Prostate cancer

  • Multiple myeloma

  • Renal cell carcinoma

• Treatment of tumor-induced hypercalcemia

D. Other Conditions

• Osteogenesis imperfecta (off-label)

• Fibrous dysplasia (investigational)

• Complex Regional Pain Syndrome (CRPS) (limited evidence)

---

5. Pharmacokinetics

• Absorption: Very poor oral bioavailability (~1%)

  • Further reduced by food, calcium, iron, magnesium, antacids

  • Must be taken on an empty stomach with water

• Distribution: Rapid binding to bone matrix

  • Long skeletal half-life (up to 10 years)

• Metabolism: Not metabolized

• Excretion: Renally excreted unchanged

  • Dose adjustment or avoidance in renal impairment (eGFR <30–35 mL/min)

---

6. Dosing and Administration Guidelines

Oral Bisphosphonates:

• Taken first thing in the morning with a full glass of water

• Must remain upright (sitting or standing) for at least 30 minutes

• Avoid eating or drinking (other than water) for 30–60 minutes

IV Bisphosphonates:

• Zoledronic acid: 5 mg yearly for osteoporosis

• Monitor renal function before infusion

• Infuse slowly over 15 minutes to reduce renal toxicity risk

---

7. Adverse Effects

Common:

• Gastrointestinal irritation (oral agents)

• Dysphagia, esophagitis, esophageal ulcers

Serious/Rare:

• Osteonecrosis of the Jaw (ONJ):

  • Higher risk with IV agents in cancer patients

  • More common with invasive dental procedures

  • Risk factors: poor dental hygiene, smoking, glucocorticoids

• Atypical Femoral Fractures:

  • Subtrochanteric or femoral shaft fractures

  • Occur with minimal trauma

  • Associated with long-term therapy (>5 years)

• Acute Phase Reaction:

  • Fever, myalgia, arthralgia after IV administration

  • Self-limiting; resembles influenza

• Renal Toxicity:

  • Zoledronic acid and pamidronate may cause dose-dependent nephrotoxicity

  • Avoid rapid infusion

• Hypocalcemia:

  • Especially in vitamin D–deficient or hypoparathyroid patients

  • Ensure adequate supplementation

---

8. Contraindications

• Hypersensitivity to bisphosphonates

• Esophageal abnormalities delaying emptying (for oral forms)

• Inability to sit or stand upright for 30–60 minutes

• Hypocalcemia

• Severe renal impairment (eGFR <30 mL/min)

---

9. Precautions

• Dental evaluation before starting IV bisphosphonates (to prevent ONJ)

• Ensure sufficient calcium and vitamin D intake

• Periodic re-evaluation of need for continued therapy after 3–5 years

• Consider a “drug holiday” in low-risk patients

---

10. Drug Interactions

• Calcium, iron, antacids, multivitamins:

  • Reduce absorption of oral bisphosphonates

  • Separate by at least 30–60 minutes

• NSAIDs:

  • Additive risk of GI ulceration

• Aminoglycosides and loop diuretics:

  • May increase risk of hypocalcemia

• Nephrotoxic agents (e.g., cisplatin, cyclosporine):

  • Risk of additive renal damage with IV bisphosphonates

---

11. Monitoring Parameters

• Bone Mineral Density (BMD):

  • DEXA scan at baseline and every 1–2 years

• Serum Calcium and Vitamin D:

  • Ensure sufficiency prior to therapy

• Renal Function:

  • Especially with IV agents

• Signs of ONJ or atypical fractures:

  • Evaluate for dental pain, groin pain, or thigh discomfort

---

12. Drug-Specific Highlights

Alendronate:

• Proven efficacy in reducing hip, vertebral, and nonvertebral fractures

• Weekly dosing improves adherence

Zoledronic Acid:

• Most potent bisphosphonate

• Annual infusion; improved adherence and consistent effect

• Oncology uses: monthly dosing in bone metastases

Ibandronate:

• Does not reduce hip fracture risk

• Monthly oral or quarterly IV option for convenience

Risedronate:

• Less acidic formulation available (Atelvia)

• Weekly or monthly dosing

---

13. Duration of Therapy and Drug Holidays

• Long skeletal retention allows for extended effects after discontinuation

• Consider “drug holiday” after 3–5 years in low-risk patients to mitigate rare adverse events

• High-risk patients (e.g., prior fractures, low T-scores) may benefit from continued treatment

---

14. Summary Table

Generic Name	Brand Name	Route	Frequency	Key Indications
Alendronate	Fosamax	Oral	Weekly/Daily	Osteoporosis, Paget’s disease
Risedronate	Actonel	Oral	Weekly/Monthly	Osteoporosis
Ibandronate	Boniva	Oral/IV	Monthly/Quarterly	Osteoporosis (vertebral only)
Zoledronic Acid	Reclast/Zometa	IV	Yearly/Monthly	Osteoporosis, Bone metastases
Pamidronate	Aredia	IV	Monthly	Bone metastases, hypercalcemia
Etidronate	Didronel	Oral	Obsolete	Paget’s disease