Introduction
Zometa (zoledronic acid) is a potent intravenous bisphosphonate medication primarily used to manage skeletal complications associated with malignancies and metabolic bone disorders. As a third-generation nitrogen-containing bisphosphonate, it represents one of the most potent inhibitors of osteoclast-mediated bone resorption available in clinical practice.
Mechanism of Action
Zometa exerts its pharmacological effects through inhibition of osteoclast-mediated bone resorption. The drug binds preferentially to bone hydroxyapatite crystals, particularly at sites of active bone remodeling. Once internalized by osteoclasts, zometa inhibits farnesyl pyrophosphate synthase in the mevalonate pathway, disrupting prenylation of GTP-binding proteins essential for osteoclast function and survival. This results in reduced osteoclast activity, induction of osteoclast apoptosis, and ultimately decreased bone resorption.
Indications
- Treatment of hypercalcemia of malignancy
- Multiple myeloma and bone metastases from solid tumors (to reduce skeletal-related events)
- Osteoporosis treatment in postmenopausal women and men at high risk of fracture
- Prevention of osteoporosis in postmenopausal women with low bone mass
- Glucocorticoid-induced osteoporosis in patients initiating or continuing systemic glucocorticoid therapy
Dosage and Administration
Hypercalcemia of malignancy: 4 mg IV over at least 15 minutes; may retreat after 7 days if serum calcium not normalized Multiple myeloma/metastatic bone disease: 4 mg IV over at least 15 minutes every 3-4 weeks Osteoporosis: 5 mg IV over at least 15 minutes once yearly Renal impairment: Adjust based on creatinine clearance:- CrCl >60 mL/min: No adjustment
- CrCl 50-60 mL/min: 3.5 mg
- CrCl 40-49 mL/min: 3.3 mg
- CrCl 30-39 mL/min: 3.0 mg
- CrCl <30 mL/min: Not recommended
Pharmacokinetics
Absorption: Administered IV only; complete bioavailability Distribution: Binds extensively to bone (approximately 60% of dose); plasma protein binding is low (22%) Metabolism: Not metabolized; does not undergo hepatic transformation Elimination: Renal excretion as unchanged drug; biphasic elimination with terminal half-life exceeding 146 hours Special populations: Clearance correlates with creatinine clearance; not dialyzableContraindications
- Hypersensitivity to zoledronic acid or other bisphosphonates
- Severe renal impairment (CrCl <30 mL/min)
- Hypocalcemia
- Pregnancy and breastfeeding
Warnings and Precautions
Renal impairment: May worsen renal function; monitor serum creatinine before each dose Osteonecrosis of the jaw: Reported incidence 1-10%; complete dental exam before initiation Atypical femoral fractures: Consider discontinuation if symptoms develop Hypocalcemia: Correct prior to administration; ensure adequate calcium and vitamin D intake Ocular inflammation: Uveitis, scleritis, and episcleritis reported Atrial fibrillation: Increased risk observed in some studiesDrug Interactions
- Aminoglycosides: Additive hypocalcemic effects
- Loop diuretics: May increase risk of hypocalcemia
- Nephrotoxic drugs: Increased risk of renal impairment
- Calcium supplements: May interfere with absorption if taken too close to infusion
Adverse Effects
Common (>10%): Fever, fatigue, anemia, nausea, vomiting, constipation, dyspnea Less common (1-10%): Hypocalcemia, hypophosphatemia, headache, insomnia, anxiety, bone pain, myalgia, arthralgia Serious (<1%): Renal impairment, osteonecrosis of the jaw, atrial fibrillation, atypical femoral fractures, ocular inflammation, anaphylaxisMonitoring Parameters
- Serum creatinine before each dose
- Serum calcium, phosphorus, and magnesium within 2 weeks after infusion
- Complete blood count regularly
- Dental examinations periodically
- Bone mineral density (for osteoporosis indication)
- Signs/symptoms of osteonecrosis of the jaw
- Monitoring for atypical femoral fractures
Patient Education
- Report any jaw pain, dental problems, or unusual thigh/hip/groin pain immediately
- Maintain adequate calcium (1200-1500 mg/day) and vitamin D (400-800 IU/day) intake
- Stay well-hydrated before and after infusion
- Inform all healthcare providers about Zometa therapy, especially before dental procedures
- Report fever, flu-like symptoms, or eye pain after infusion
- Adhere to recommended dosing intervals
- Notify physician if pregnancy is suspected or planned
References
1. Coleman RE, et al. Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of bone resorption. J Clin Oncol. 2008;26(4):642-649. 2. Black DM, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809-1822. 3. Zometa® (zoledronic acid) prescribing information. Novartis Pharmaceuticals Corporation. 4. Saad F, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879-882. 5. Kyle RA, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25(17):2464-2472.