Preclinical Perspectives on Bisphosphonate Renal Safety

Abstract

Renal insufficiency is not rare in cancer patients who may receive nephrotoxic medications as antineo-plastic agents or for comorbid conditions. Thus, the choice of a particular bisphosphonate for patients with metastatic bone disease should be based not only on efficacy but also on the risk for renal deterioration. Some i.v. bisphosphonates have been associated with occasional renal toxicity in the clinical setting. Preclinical studies have also shown that there may be considerable differences among bisphosphonate renal safety profiles. Comparative studies show variations in the risk for histopathologic damage and the ability to cause cumulative toxicity during intermittent dosing. Reasons for the differences among bisphosphonates are not fully understood; however, research shows that they may be influenced by pharmacokinetic properties such as renal tissue half-life or protein binding and intracellular potency. Further preclinical analyses are needed to confirm and evaluate differences among bisphosphonates.

Treatment of Ionized Hypercalcemia in 12 Cats (2006–2008) Using PO‐Administered Alendronate

“…Similar signs have been reported in humans taking bisphosphonates and are believed to be the result of a systemic inflammatory response, an effect that is more common after first dose IV administration 22, 23. Other adverse effects reported in humans are esophageal irritation and ulceration because of prolonged esophageal mucosa‐drug contact time and potential subsequent stricture24, 25; gastrointestinal signs (inappetence, vomiting, diarrhea, abdominal pain)26; osteonecrosis of the mandible and maxilla27; acute, and chronic kidney failure (especially with higher doses and rapid parenteral administration)28; nephrotic syndrome29; and, electrolyte abnormalities (hypophosphatemia, hypocalcemia, hypomagnesemia) 30. Osteonecrosis of the jaw has been reported in 2 Beagle dogs that received long‐term PO alendronate treatment.…”

Bone Loss and Fracture Risk Associated with Cancer Therapy

“…Physicians should consider the potential risks and benefits of continuing bisphosphonate therapy in patients with hypercalcemia of malignancy who exhibit severe renal impairment. Other risk factors that may affect renal toxicity of bisphosphonates include dehydration and the use of other nephrotoxic drugs [52]. Dose adjustment of zoledronic acid is not necessary for patients with hypercalcemia and mild-to-moderate renal impairment (serum creatinine <400 μmol/l or <4.5 mg/dl) prior to initiating therapy with zoledronic acid [53].…”

Long-term renal safety profile of ibandronate 6 mg infused over 15 minutes

“…The primary endpoint was the per centage of patients with a serum creatinine increase of ≥44.2 mmol/l (= 0.5 mg/dl) from core baseline. Results: Fourteen patients entered the followup phase and re ceived a median of 16 infusions (range: [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. No patient reached the primary endpoint.…”