Zoledronate

Bisphosphonates (BP) are today the first line treatment of benign and malignant bone diseases. As pyrophosphate analogues (Fig. 3), BP accumulate in bone and are taken up by osteoclasts. Once in the cell, the nitrogen-containing BP (N-BP) such as Alendronate, Risedronate, Ibandronate and Zoledronate effectively inhibit osteoclast resorption and induce cell... 

Bone Metabolism. Figure 3 Chemical structure of pyrophosphate (a) and the bisphosphonates etidronate (b), clodronate (c), pamidronate (d), ibandronate (e). alendronate (f), risedronate (g), zoledronate (h). 

R (2002) Novel antiangiogenic effects of the bisphosphonate compoimd zoledronic acid. J Pharmacol Exp Then 302 (3) 1055-61. 

Zoledronic acid (Zometa , available as generic) 4-8 mg Days Weeks 1-5 mg/dL... 

There is considerable interest in using injectable bisphosphonates, such as pamidronate and zoledronic acid, in patients unable to tolerate or absorb oral bisphosphonates. Zoledronic acid in particular has a potential advantage of once-yearly dosing. Currently, neither drug has received FDA approval for this indication. Ibandronate has recently been approved for this indication. 

For women whose breast cancer has metastasized to bone, bisphosphonates are recommended, in addition to chemotherapy or endocrine therapy, to reduce bone pain and fractures.28,64 Pamidronate (90 mg) and zoledronate (4 mg) can be given intravenously once each month. These bisphosphonates are given in combination with calcium and vitamin D. 

Pamidronate and zoledronic acid are used most commonly and are potent inhibitors of osteoclast activity.29 The choice of bisphosphonate is a difficult one zoledronic acid is more efficacious in terms of response rate and longer duration of nor-mocalcemia but is approximately four times more expensive.30 Regardless of selection, the bisphosphonates should be administered at diagnosis owing to their delayed onset of action. 

Zoledronic acid 4 mg IV over 15 minutes 24-48 hours 4+ weeks Greater than 1 mg/dL cause fever, renal dysfunction pamidronate less expensive. 

Alendronate, risedronate, and oral ibandronate are FDA approved for prevention and treatment of postmenopausal osteoporosis. IV ibandronate and zoledronic acid are indicated only for treatment of postmenopausal women. Risedronate and alendronate are also approved for male and glucocorticoid-induced osteoporosis. 

Intravenous bisphosphonates Ibandronate (Boniva) Zoledronic add0 (Reclast) 5 mg IV infusion yearly... 

Bisphosphonates such as pamidronate and zoledronic acid may prevent skeletal morbidity, such as pathologic fractures and spinal code compression, when used for hormone-refractory prostate cancer in patients with clinically significant bone loss. Usual dosages are pamidronate, 90 mg every month, and zoledronic acid, 4 mg every 3 to 4 weeks. 

Zoledronate 4-8 mg IV over 15 minutes 1-2 days Renal insufficiency Fever, fatigue, skeletal pain... 

AP23451 administration to mice inoculated with MDA-231 breast cancer cells effectively prevents metastasis-induced osteolysis similar to bisphosphonate zoledronic (Zometa ). However, it also significantly reduces the volirme of tumor cells inside the bone marrow cavities of the mice as opposed to a lack of inhibitory effect on tirmor cell volume in mice treated with zoledronic acid. AP23588 is also a bone-targeted Src kinase inhibitor which has been determined to possess both anti-resorptive and anabohc properties in vitro with respect to reducing osteoclast activity and stimulating osteoblast activity, respectively. 

Powder for injection 4 mg zoledronic acid anhydrous Rx) Zometa (Novartis)... 

Hypercalcemia of malignancy (HCM) For the treatment of FICM (zoledronic acid) in conjunction with adequate hydration for the treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases (pamidronate patients with epidermoid or nonepidermoid tumors respond to pamidronate) for FICM that persists after adequate hydration has been restored (zoledronic acid). 

Multiple myeloma and bone metastases of solid tumors (zoledronic acid) For the treatment of multiple myeloma and bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. 

Dose The maximum recommended dose in hypercalcemia of malignancy (albumin-corrected serum calcium at least 12 mg/dL [3 mmol/L]) is 4 mg. The 4 mg dose must be given as a single dose IV infusion over not less than 15 minutes. Adequately rehydrate patients prior to administration of zoledronic acid. 

Retreatment Retreatment with 4 mg zoledronic acid may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for a full response to the initial dose. 

Multiple myeloma and metastatic bone lesions from solid tumors- The recommended dose of zoledronic acid in patients with multiple myeloma and metastatic bone lesions from solid tumors is 4 mg infused over 15 minutes every 3 or 4 weeks. Also give patients an oral calcium supplement of 500 mg and a multiple vitamin containing 400 units vitamin D daily. 

Renal function impairment- Upon treatment initiation, the recommended zoledronic acid doses for patients with reduced renal function (mild to moderate renal impairment) are listed in the following table. These doses are calculated to achieve the same AUC as that achieved in patients with Ccr of 75 mL/min. Ccr is calculated using the Cockcroft-Gault formula. 

Recommended Zoledronic Acid Dose for Patients with Mild to Moderate... 

During treatment, measure serum creatinine before each zoledronic acid dose and withhold treatment for renal deterioration. In the clinical studies, renal deterioration was defined as follows ... 

In the clinical studies, zoledronic acid treatment was resumed only when the creatinine returned to within 10% of the baseline value. Reinitiate zoledronic acid at the same dose as that prior to treatment interruption. 

Asthma (zoledronic acid) While not observed in clinical trials with zoledronic acid, administration of other bisphosphonates has been associated with bronchoconstriction in aspirin-sensitive asthmatic patients. Use zoledronic acid with caution in patients with aspirin-sensitive asthma. 

Zoledronic acid- Single doses of zoledronic acid should not exceed 4 mg and the duration of infusion should be no less than 15 minutes. Zoledronic acid treatment is not recommended in patients with bone metastases with severe renal impairment. Patients who receive zoledronic acid should have serum creatinine assessed prior to each treatment. 

Pregnancy Category D (zoledronic acid) Category C (alendronate, oral and IV etidronate, pamidronate, risedronate, and tiludronate). 

Lactation It is not known whether these drugs are excreted in breast milk. Because zoledronic acid binds to bone long-term, do not administer to a nursing woman. Children Safety and efficacy for use in children have not been established. Children have been treated with etidronate at doses recommended for adults, to prevent heterotopic ossifications or soft tissue calcifications. 

Monitoring Carefully monitor standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, magnesium, and potassium following pamidronate and zoledronic acid initiation. Also, closely monitor electrolytes, creatinine as well as CBC, differential and hematocrit/hemoglobin. Carefully monitor patients who have preexisting anemia, leukopenia or thrombocytopenia in the first 2 weeks following treatment. 

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