doses higher than those recommended (see section 4.2) should be carefully monitored, since renal function impairment (including renal failure) and serum electrolyte (including calcium, phosphorus and magnesium) abnormalities have been observed. In the event of hypocalcaemia, calcium gluconate infusions should be administered as clinically indicated.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05BA08
Zoledronic acid belongs to the class of bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclastic bone resorption.
The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting the formation, mineralisation or mechanical properties of bone.
In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses several anti-tumour properties that could contribute to its overall efficacy in the treatment of metastatic bone disease. The following properties have been demonstrated in preclinical studies:
- In vivo: Inhibition of osteoclastic bone resorption, which alters the bone marrow microenvironment, making it less conducive to tumour cell growth, anti-angiogenic activity and anti-pain activity.
- In vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity on tumour cells, synergistic cytostatic effect with other anti-cancer drugs, anti-adhesion/invasion activity.
Clinical trial results in the prevention of skeletal related events in patients with advanced malignancies involving bone
The first randomised, double-blind, placebo-controlled study compared zoledronic acid 4 mg to placebo for the prevention of skeletal related events (SREs) in prostate cancer patients. Zoledronic acid 4 mg significantly reduced the proportion of patients experiencing at least one skeletal related event (SRE), delayed the median time to first SRE by > 5 months, and reduced the annual incidence of events per patient - skeletal morbidity rate. Multiple event analysis showed a 36% risk reduction in developing SREs in the zoledronic acid 4 mg group compared with placebo. Patients receiving zoledronic acid 4 mg reported less increase in pain than those receiving placebo, and the difference reached significance at months 3, 9, 21 and 24. Fewer zoledronic acid 4 mg patients suffered pathological fractures. The treatment effects were less pronounced in patients with blastic lesions. Efficacy results are provided in Table 3.
In a second study including solid tumours other than breast or prostate cancer, zoledronic acid 4 mg significantly reduced the proportion of patients with an SRE, delayed the median time to first SRE by > 2 months, and reduced the skeletal morbidity rate. Multiple event analysis showed 30.7% risk reduction in developing SREs in the zoledronic acid 4 mg group compared with placebo. Efficacy results are provided in Table 4.
Table 3: Efficacy results (prostate cancer patients receiving hormonal therapy)
Any SRE (+TIH)
Fractures*
Radiation therapy to bone
zol
