What are the recommended dosing regimens for bisphosphonates (alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), zoledronic acid (Reclast), pamidronate (Aredia)) for osteoporosis, Paget disease, malignancy‑related bone disease, and hypercalcemia, and how should impaired renal function affect their use?

Bisphosphonate Dosing Regimens

For osteoporosis, use alendronate 70 mg weekly or zoledronic acid 5 mg annually as first-line therapy; for multiple myeloma and malignancy-related bone disease, use zoledronic acid 4 mg every 3-4 weeks (or every 3 months after initial treatment); for Paget disease, use alendronate 40 mg daily or risedronate 30 mg daily for 3-6 months; and for hypercalcemia of malignancy, use zoledronic acid 4 mg as a single infusion. 1

Osteoporosis Treatment

Standard Dosing Regimens

Oral bisphosphonates (first-line):

• Alendronate: 70 mg once weekly (or 10 mg daily) for treatment; 35 mg weekly (or 5 mg daily) for prevention 2, 1
• Risedronate: 35 mg once weekly (or 5 mg daily) for treatment 1, 3
• Ibandronate: 150 mg once monthly 1, 4

Intravenous bisphosphonates (for patients intolerant of oral formulations):

• Zoledronic acid: 5 mg annually via IV infusion over at least 15 minutes 5, 1
• Ibandronate: 3 mg IV every 3 months 1, 3

Treatment Duration and Monitoring

• Treat for 5 years, then reassess fracture risk to determine whether to continue or initiate a drug holiday 2, 5
• Do not routinely monitor BMD during the initial 5-year treatment period, as patients benefit even if BMD does not increase 2
• After 5 years, consider discontinuation in low-risk patients; continue in high-risk patients (prior fracture, very low BMD, age >75) 1, 5

Renal Dosing Adjustments

• Alendronate: No adjustment needed if eGFR ≥35 mL/min/1.73 m²; contraindicated if eGFR <35 mL/min/1.73 m² 2
• Zoledronic acid: Reduce dose if CrCl 30-60 mL/min; contraindicated if CrCl <30 mL/min 1, 5
• Oral bisphosphonates have better renal safety than IV formulations in patients with lower creatinine clearance 1

Multiple Myeloma and Malignancy-Related Bone Disease

Standard Dosing

• Zoledronic acid: 4 mg IV over 15 minutes every 3-4 weeks for up to 2 years 1
• Pamidronate: 90 mg IV over 4-6 hours every 3-4 weeks 1
• After initial 2-year period, consider reducing frequency to every 3 months in patients with stable/responsive disease 1

Renal Impairment Dosing

• Severe renal impairment (CrCl <30 mL/min or SCr >3.0 mg/dL): Use pamidronate 90 mg over 4-6 hours with dose reduction consideration 1
• Zoledronic acid: Reduce dose for CrCl 30-60 mL/min; avoid if CrCl <30 mL/min 1
• Monitor serum creatinine before each dose; withhold if unexplained deterioration occurs 1

Alternative Agent

• Denosumab: 120 mg subcutaneously every 4 weeks; preferred in patients with renal disease (no dose adjustment required) 1

Paget Disease of Bone

Standard Dosing Regimens

• Alendronate: 40 mg daily for 3-6 months 3, 6
• Risedronate: 30 mg daily for 3-6 months 3, 7
• Zoledronic acid: 5 mg IV single infusion (most effective; normalizes alkaline phosphatase in >70% of patients) 3
• Pamidronate: 30-60 mg IV weekly for several weeks 6

Alternative Low-Dose Regimen

• In select patients, alendronate 70 mg weekly or risedronate 35 mg weekly (osteoporosis doses) can achieve remission in 84-87% of cases, though this is below guideline-recommended doses 7
• If remission not achieved, increase to alendronate 140 mg weekly or risedronate 70 mg weekly 7

Hypercalcemia of Malignancy

Preferred Regimen

• Zoledronic acid: 4 mg IV over 15 minutes as a single dose (most effective) 1, 3
• Pamidronate: 60-90 mg IV over 2-4 hours as a single dose 6
• Ibandronate: 2-4 mg IV as a single dose 3

Adjunctive Measures

• Aggressive hydration with normal saline before bisphosphonate administration 1
• Consider adding steroids and/or calcitonin for severe cases 1

Cancer Treatment-Induced Bone Loss

Aromatase Inhibitor or Androgen Deprivation Therapy

• **Initiate treatment if T-score <-2.0** OR if T-score ≥-2.0 with ≥2 risk factors (age >65, smoking, BMI <24, family history of hip fracture, prior fragility fracture, glucocorticoid use >6 months) 2
• Zoledronic acid: 4 mg IV every 6 months 2, 5
• Alendronate: 70 mg weekly 2
• Continue for duration of endocrine treatment or up to 5 years 2

Critical Pre-Treatment Requirements

All Bisphosphonates

• Correct vitamin D deficiency before treatment to prevent severe hypocalcemia (target 25(OH)D ≥30 ng/mL) 1, 5
• Ensure adequate calcium intake (1000-1200 mg daily) and vitamin D supplementation (800-1000 IU daily) 1, 5
• Dental examination and prophylactic care before starting therapy to reduce osteonecrosis of the jaw risk 1

Intravenous Bisphosphonates

• Check creatinine clearance before each infusion 1, 5
• Ensure adequate hydration before administration 5, 8
• Monitor serum calcium, electrolytes, phosphate, and magnesium before each infusion 5

Administration Guidelines

Oral Bisphosphonates

• Take on empty stomach with 6-8 oz plain water upon arising for the day 2
• Remain upright (sitting or standing) for at least 30 minutes after administration 2
• Do not eat, drink, or take other medications for at least 30 minutes 2
• Contraindicated in patients with esophageal emptying disorders or inability to sit/stand upright 1

Intravenous Bisphosphonates

• Zoledronic acid: Infuse over at least 15 minutes; never infuse faster as this increases acute phase reactions and renal toxicity 5, 8
• Pamidronate: Infuse over 2-4 hours; infusion times <2 hours should be avoided 1

Common Pitfalls and Adverse Effects

Osteonecrosis of the Jaw (ONJ)

• Incidence with osteoporosis dosing: <1-28 per 100,000 person-years 2, 5
• Incidence with oncology dosing (4 mg every 3-4 weeks): 1-10% 1
• Risk factors: dental extractions, poor oral hygiene, duration >2 years 1, 2
• Advise against unnecessary invasive oral surgery during therapy 1

Acute Phase Reactions (IV Bisphosphonates)

• Occur in 25-40% of patients after first zoledronic acid infusion (flu-like symptoms, fever, myalgia, arthralgia) 5
• Typically resolve within 3-4 days; decrease with subsequent infusions 5
• Premedicate with acetaminophen or NSAIDs; routine corticosteroid prophylaxis is not recommended 5

Renal Toxicity

• Risk related to dose, infusion rate, and hydration status 1, 8
• Withhold therapy if unexplained renal deterioration occurs; resume when creatinine returns to within 10% of baseline 1
• Zoledronic acid and pamidronate can cause acute tubular necrosis or focal segmental glomerulosclerosis 8

Atypical Femoral Fractures

• Rare complication associated with treatment duration >3-5 years 5
• Incidence: 3.0-9.8 per 100,000 patient-years 2

Hypocalcemia

• More pronounced with denosumab than bisphosphonates 1
• Monitor serum calcium regularly; supplement calcium and vitamin D 1, 5

Treatment Failure Management

• If fracture occurs ≥12 months after starting therapy OR significant BMD loss after 1-2 years, switch to another class (IV bisphosphonate, denosumab, romosozumab, or teriparatide/abaloparatide) 2
• Do not switch directly from denosumab to teriparatide/abaloparatide due to transient hip/spine BMD loss 2
• Teriparatide/abaloparatide after long-term bisphosphonate use produces blunted but measurable anabolic response 2