SAT-780 - Biopsy-Proven Podocytopathy with Nephrotic Syndrome Following Zoledronic Acid

Background:
Zoledronic acid is commonly used in the management of osteoporosis, including as transition therapy after long-term denosumab use to mitigate rebound bone loss. Although zoledronic acid is generally considered renally safe in patients with preserved kidney function, rare cases of glomerular injury have been reported. We describe a case of focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome developing after zoledronic acid infusion.

Case:
A 65-year-old male with history of rheumatoid arthritis on chronic glucocorticoids since 2000, secondary adrenal insufficiency, and osteoporosis was being followed for bone health management. Osteoporosis was initially diagnosed on DEXA screening due to prolonged steroid exposure and history of multiple vertebral compression fractures. He received denosumab for over 6 years before transitioning to zoledronic acid infusions. Zoledronic acid was initiated in 12/2023, with a second infusion administered in 1/2025.

Following the second infusion, the patient developed hypoalbuminemia, acute kidney injury, and nephrotic syndrome, requiring hospitalization in 3/2025. His urine protein-to-creatinine ratio peaked at 15 g/g with a preserved renal function (baseline eGFR 78-97 mL/min and creatinine 0.8 mg/dL). A renal biopsy in 3/2025 demonstrated diffuse podocyte foot processes effacement consistent with podocytopathy, without immune complex or amyloid disease; these findings were suggestive of a drug-associated FSGS. Zoledronic acid was discontinued based on temporal association, biopsy findings, and exclusion of secondary etiologies. The patient also required multiple courses of high-dose prednisone for recurrent nephrotic syndrome, now being weaned.

DEXA scan in 4/2023 showed osteopenia (lowest T-score -1.3 at the femoral neck) with imaging-confirmed grade 2 vertebral compression fracture. Baseline bone turnover marker CTX (C-terminal telopeptide of type I collagen) prior to zoledronic acid initiation was < 50 pg/mL (9/2023), increased to 765 pg/mL (4/2025) after zoledronic acid discontinuation, and later decreased to 278 pg/mL (10/2025). Given the ongoing glucocorticoid exposure and persistent nephrotic syndrome, the patient preferred reinitiating denosumab and repeating the DEXA scan once renal function stabilizes.

Conclusion:
This case highlights an uncommon but clinically significant complication of intravenous bisphosphonates: biopsy-proven podocytopathy with nephrotic syndrome following zoledronic acid, despite preserved baseline renal function. The observed decline in CTX likely reflects glucocorticoid- and illness-related suppression of bone turnover rather than therapeutic effects. Thus, clinicians should be advised to monitor for proteinuria and hypoalbuminemia after intravenous bisphosphonates use, even in the absence of pre-existing chronic kidney disease.

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