For the treatment of hypercalcemia of malignancy. Also for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. In May of 2007, the drug was approved for treatment of Paget’s Disease.
The action of zoledronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Zoledronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates such as zoledronate appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.
There is no experience of acute overdose. Two patients received zoledronate (32 mg) over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia.
Poorly absorbed (oral absorption is about 1% of what intravenous absorption is).
146 hours
In 64 patients with cancer and bone metastases, on average (± s.d.) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-Day 2.
* Renal cl=3.7 +/- 2.0 L/h