Why oral and IV differ

• Oral bisphosphonates (alendronate, risedronate, ibandronate) irritate the mucosa directly. They cause esophagitis and esophageal ulcers, which are the usual source of any GI bleed. Patients are told to stay upright after a dose for this reason. - Lippincott Illustrated Reviews: Pharmacology, Ch. Summary
• Goodman & Gilman says the same. Heartburn, esophagitis and abdominal pain are listed for oral agents, and oral bisphosphonates should not be given to patients with active upper GI disease. - Goodman & Gilman's, Adverse Effects
• IV zoledronic acid bypasses the esophagus and stomach. For this reason it is used as an alternative in patients who cannot tolerate oral therapy. The HSS rheumatology guidance says it is not associated with GI irritation.
• Even for oral agents, large RCTs show little excess risk when they are taken correctly. In one alendronate trial, upper GI events were 47.5% vs 46.2% with placebo, and esophageal ulcers were 0.2% in both arms. - Rheumatology 2022 (Elsevier), Side Effects of Antiresorptive Agents

What IV zoledronate does cause

• Acute phase reaction. About 10% of patients get a flu-like illness for 24 to 48 hours. It brings fever, myalgia, arthralgia and nausea. - Rheumatology 2022 (Elsevier)
• Nausea, vomiting, abdominal discomfort and diarrhea. These are usually short-lived. Goodman & Gilman describes them for pamidronate infusions, mainly with faster or more concentrated infusions.
• Hypocalcemia and renal toxicity. Give the infusion over at least 15 minutes and check renal function first. Avoid it if eGFR is below 35. - Goodman & Gilman's; Goldman-Cecil Table 228-1

If a patient on IV zoledronate presents with UGIB

1. NSAIDs, aspirin, anticoagulants or antiplatelets. These are the commonest culprits and are often used together with bone-pain treatment.
2. Glucocorticoids. Patients on steroids often get bisphosphonates, and steroids add to ulcer risk, especially with NSAIDs. - Harrison's 22E, Glucocorticoids
3. Cancer patients. Zoledronic acid at 4 mg is given to them for bone metastases or hypercalcemia. They often have other bleeding risks, such as chemotherapy mucositis, stress ulcers, thrombocytopenia, coagulopathy, tumor involvement and H. pylori.
4. Recent or concurrent oral bisphosphonate. An overlapping oral dose can explain esophagitis.
5. Hypocalcemia or renal failure. Uremia causes platelet dysfunction and raises bleeding risk. Zoledronate can worsen kidney function, so check creatinine and calcium.
6. Severe acute phase reaction. Repeated vomiting could cause a Mallory-Weiss tear. This is a plausible mechanism, not a documented one.

Practical points

• Treat the bleed as usual: resuscitate, give a PPI and do endoscopy.
• Record the timing of the infusion relative to symptom onset. Report it through pharmacovigilance if you suspect a link.
• A past UGIB or GI disease is not a contraindication to IV zoledronate. It is often the reason to choose IV over oral.
• Give calcium and vitamin D, and correct hypocalcemia before the infusion.