In August 2007, the Food and Drug Administration approved zoledronic acid (Reclast) with a new indication for osteoporosis treatment in postmenopausal women. Reclast, an intravenous bisphosphonate from Novartis Pharmaceuticals, was previously indicated for treatment of Paget's disease of bone, a metabolic bone disease that causes accelerated bone remodeling and excessive bone resorption followed by excessive abnormal bone formation, often resulting in bone deformity.
Fifty percent of women and 25% of men over 50 years of age will have an osteoporosis-related fracture during her or his lifetime. Osteoporosis is responsible for more than 1.5 million fractures annually1, including:
* over 300,000 hip fractures
* 700,000 vertebral fractures
* 250,000 wrist fractures
* 300,000 fractures at other sites.1
In clinical studies of postmenopausal women with osteoporosis, Reclast was found to reduce the incidence of fractures (hip, vertebral, and nonvertebral osteoporosis-related fractures).2
Indications
Reclast is indicated for treatment of osteoporosis in postmenopausal women. The efficacy and safety of Reclast in the treatment of postmenopausal osteoporosis was demonstrated in a randomized, double-blind, placebo-controlled, multinational study of 7,736 women 65 to 89 years of age.2
Mechanism of Action
Reclast is a bisphosphonate and acts primarily on bone as an inhibitor of osteoclast-mediated bone resorption.2 The selective action of zoledronic acid on bone is based on its high affinity for mineralized bone. Zoledronic acid administered intravenously rapidly partitions to bone and localizes at sites of high bone turnover. The main molecular target of zoledronic acid is the enzymatic activity in osteoclasts. Because of its high binding affinity to bone mineral, zoledronic acid has a relatively long duration of action.2
Drug Metabolism
Pharmacokinetic properties of Reclast are not based on studies with osteoporotic postmenopausal women or patients with Paget's disease of the bone. Information related to drug distribution, metabolism, and elimination is derived from animal studies and from the use of zoledronic acid in patients with cancer and bone metastases.
Zoledronic acid is administered by intravenous infusion and shows a rapid decrease in plasma concentration after distribution. Less than 1% of the drug is detectable after 24 hours postadministration.2 Zoledronic acid has a low affinity for blood components and has only moderate protein binding in human plasma.
Zoledronic acid does not inhibit cytochrome P450 enzymes and does not undergo biotransformation. The drug is either taken up by bone or eliminated unchanged in the feces and urine, which suggests that zoledronic acid is not metabolized.2
Excretion of zoledronic acid unbound to bone appears to be predominantly through the kidneys and seems to be partially dependent on a patient's kidney function as measured by creatinine clearance.
Contraindications
Reclast is contraindicated in patients with any history of hypersensitivity reactions to zoledronic acid. The drug is also contraindicated for any patient with current hypocalcemia. Oncology patients receiving Zometa, another form of zoledronic acid, should not receive Reclast.
Patients with preexisting hypocalcemia and disturbances of mineral metabolism (hypoparathyroidism, thyroid surgery, parathyroid surgery; malabsorption syndromes, excision of small intestine) must be effectively treated before initiating therapy with Reclast.2 Monitoring calcium, phosphorus, and magnesium levels is highly recommended for these patients.
Because the drug is excreted through the kidney, Reclast is not recommended for use in patients with severe renal impairment (creatinine clearance lower than 35 mL/ minute) due to lack of adequate clinical trials in this population.2 Patients (especially those on diuretics) should also be appropriately hydrated prior to administration of Reclast and used cautiously with concomitant use of other nephrotoxic drugs. Monitoring serum creatinine before each Reclast dose is recommended. Race, hepatic function, and age do not appear to be characteristics requiring special monitoring. Reclast is a pregnancy Category D drug and has a potential for alterations to fetal bone development; therefore, it is contraindicated in pregnant women or those who wish to become pregnant. It is unknown whether Reclast is excreted in breast milk, but the manufacturer suggests that this drug not be administered to nursing women. The drug has not been studied in the pediatric population.2
Adverse Reactions
The Reclast clinical trial lasted 3 years with 3,862 patients receiving a once-annual dose. All women in the study also received 1,000 to 1,500 mg of elemental calcium plus 400 to 1,200 international units of vitamin D supplementation daily.
The incidence of serious adverse events was 29.2% in the Reclast group and 30.1% in the placebo group (see Table: "Adverse Reactions Occurring in Greater Than 2% of Postmenopausal Osteoporosis Patients"). Withdrawal from the study due to adverse events was 5.4% and 4.8% for the Reclast and placebo groups, respectively.2 The most common adverse reactions in the treatment group, significantly different than the placebo group, included pyrexia, myalgia, headache, arthralgia, and pain in extremity. Osteonecrosis of the jaw has been reported in patients treated with bisphosphonates, including zoledronic acid. A dental examination should be considered before treatment with bisphosphonates in patients with a history of concomitant risk factors (cancer, chemotherapy, corticosteroids, poor oral hygiene).2
Although they occurred more than a month after treatment, the potentially significant adverse event of atrial fibrillation was seen in 1.3% of the Reclast-treated group (versus 0.5% in the placebo group). Although it is not known if there is a causal association between atrial fibrillation and bisphosphonate therapy3, practitioners are advised to monitor for this potential adverse event and examine the results of future studies.
Dosage and Administration
For postmenopausal women with osteoporosis, Reclast is administered as a 5 mg once-a-year intravenous infusion.2 The room temperature solution should be inspected for particulate matter or discoloration, and the infusion should be given over at least 15 minutes.2 To moderate possible acute-phase reaction symptoms (fever, headache, muscle aches), patients should receive appropriate doses of acetaminophen or ibuprofen following Reclast infusion. In addition, to minimize potential renal impairment, patients should be adequately hydrated prior to initiation of therapy.
Patients receiving Reclast for osteoporosis treatment should maintain an adequate intake of calcium (1,200 mg daily) and vitamin D (400 to 800 international units daily) either through diet or supplements. Hypocalcemia is a potential risk in patients receiving bisphosphonate treatment.
Reclast is a pregnancy Category D drug and should not be used in pregnant women or in nursing mothers. No precautions are needed for administration of Reclast specifically due to advanced age. However, renal function commonly declines in the elderly and practitioners are advised to monitor renal function.
The cost for once-yearly Reclast infusion is approximately $1,300. This is compared to the other intravenous bisphosphonate, ibandronate (Boniva), given once every 3 months for an approximate annual cost of $2,000. The oral bisphosphonate risedronate (Actonel), with a new twice-a-month dosing, costs approximately $1,100 per year.3
Special Instructions
Patients receiving Reclast should advise their practitioner of medications and supplements they are taking, especially those that may impact renal function. Female patients should be warned not to become pregnant or to breastfeed while receiving Reclast therapy. Patients should hydrate themselves adequately (at least two glasses of fluid such as water) a few hours before expected drug infusion. Adequate calcium and vitamin D intake is important in women with osteoporosis, and patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels.2
Acetaminophen or ibuprofen is recommended after receiving Reclast to moderate possible infusion reaction. If flu-like symptoms persist more than a week, patients should contact their provider. Persistent pain or new mouth or jaw symptoms should also be reported due to a potential, albeit low, risk of osteonecrosis of the jaw associated with zoledronic acid use.
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