Zoledronic Acid

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals

Sparingly soluble

3.27e+00 g/L

Breast Feeding; Lactation; Bisphosphonates; Bone Density Conservation Agents; Diphosphonates;

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

EMA approved medicines: Human medicine

Warning

H317 (100%): May cause an allergic skin reaction [Warning Sensitization, Skin]

P261, P264+P265, P272, P280, P302+P352, P305+P351+P338, P321, P333+P317, P337+P317, P362+P364, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

The commonly reported adverse reactions include pyrexia, headache, myalgia, pain in extremities, and arthralgia. Significant adverse effects associated with zoledronate include hypocalcemia, secondary hyperparathyroidism, acute phase response (APR), renal injury, atypical femur fractures, osteonecrosis of the jaw (ONJ), atrial fibrillation, and ocular inflammation.

In the event of toxicity or overdose, no reversal agents are approved by the FDA for this drug. In a case report, a pediatric patient with osteogenesis imperfecta experienced a substantial 15-fold overdose of zoledronate. The patient received 4 mg (0.37 mg/kg) instead of the intended 0.27 mg (0.025 mg/kg) dosage, resulting in severe hypocalcemia and hypophosphatemia, necessitating calcium and phosphorus supplementation with ergocalciferol administration. Despite supportive care and hemodialysis initiation to address electrolyte imbalances and potentially eliminate excess zoledronate, the patient experienced multiple episodes of nonsustained ventricular tachycardia. This case underscores the need for prolonged monitoring and electrolyte supplementation in pediatric Zoledronate overdose cases to address potential complications, including severe hypocalcemia and hypophosphatemia.

M05BA08

M - Musculo-skeletal system

QM - Musculo-skeletal system

M05BA08

Zoledronic acid is a third generation, nitrogen containing bisphosphonate that inhibits osteoclast function and prevents bone resorption. The therapeutic window is wide as patients are unlikely to suffer severe effects from overdoses and the duration of action is long. Patients should be counselled regarding the risk of electrolyte deficiencies, renal impairment, osteonecrosis of the jaw, atypical femoral fractures, bronchoconstriction, hepatic impairment, hypocalcemia, and embryo-fetal toxicity.

Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Etidronic acid also inhibits V-ATPases in the osteoclast, though the exact subunits are unknown, preventing F-actin from forming podosomes. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. Nitrogen containing bisphosphonates such as zoledronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate. These components are essential for post-translational prenylation of GTP-binding proteins like Rap1. The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis. zoledronate also activated caspases which further contribute to apoptosis.