The first new treatment for Paget's disease of bone to be approved by the US Food and Drug Administration (this summer) in almost 10 years has been found to be as effective as standard therapy but offers an advantage in terms of ease of use. This intravenous (IV) bisphosphonate, zoledronic acid (Reclast), is the first therapy that can be given as a single-dose infusion for Paget's disease, in contrast to current oral therapy that must be taken daily for up to 6 months, or another IV therapy that requires multiple infusions (Table).

The drug has since also been approved for the treatment of postmenopausal osteoporosis, becoming the first once-yearly injection for this indication.

In clinical trials, zoledronic acid has been shown to be more effective, with a faster onset of action, and is more likely to induce remission than oral risedronate sodium (Actonel). It avoids the adherence problems associated with oral bisphosphonates, which must be taken on an empty stomach, with a glass of water, and which require patients to remain upright for at least 30 minutes.

Paget's Disease

Paget's disease is the second most common metabolic disease of bone, after osteoporosis.

The disease occurs primarily in patients between the ages of 45 and 50 years; about 1 million patients older than 65 years in the United States have the disease.

The impact of Paget's disease on quality of life can be devastating. In addition to bone pain and skeletal deformities, such as bowed arms and legs or enlarged head, complications can include arthritis, neurologic manifestations (hearing loss, spinal stenosis), fractures and malunion, and rarely osteosarcoma.

The major culprit in Paget's disease is the osteoclast. Such cells are increased in size and in number, with a greater number of nuclei. They are quite active in bone resorption, followed by osteoblasts, which lay down bone that is ultimately structurally abnormal and weaker than nonpagetic bone.

The cause of Paget's disease is unknown, but it is thought to develop at 1 or more skeletal sites as a result of a slow viral infection in a genetically susceptible individual.

Many patients are asymptomatic. In many cases, the diagnosis is made based on finding an elevated alkaline phosphatase enzyme level in a blood chemistry screening profile, in the absence of other liver enzyme abnormalities. Paget's disease can also be diagnosed by radiographic findings when a radiograph is ordered for other medical or surgical reasons.

Who Should Be Treated?

There is general agreement that treatment is indicated in the following situations:

• Pain that is clearly related to Paget's disease
• Obvious deformity or involvement of a long bone or a weight-bearing bone (to prevent progressive deformity and disease progression)
• Disease involving the spine or skull (to prevent neurologic complications)
• Extensive disease
• To reduce the vascularity of pagetic bone in a patient who is scheduled for surgery at a pagetic site.

Experts suggest that in an asymptomatic patient who has an area of critical involvement, such as a long bone or weight-bearing bone, it is wise to intervene immediately rather than wait until the patient becomes symptomatic.

Compared with etidronate disodium (the first bisphosphonate approved for treatment of Paget's disease), pamidronate disodium (Aredia) is 100 times as potent, alendronate sodium (Fosamax) is 700 times, risedronate sodium is 1000 times as potent, and zoledronic acid is about 10,000 times as potent.

The Evidence

Approval for zoledronic acid for Paget's disease of bone was based on two 6-month studies that randomized 357 men and women (mean age, 70 years) with moderate-to-severe disease to 1 infusion of zoledronic acid or to 2 months of oral risedronate, a current standard therapy (N Engl J Med. 2005;353:898-908). One infusion of zoledronic acid acted more rapidly and increased the incidence of responses and remissions. The response rate was greater in those treated with zoledronic acid (96% at end of study versus 74% with risedronate). In addition, alkaline phosphatase levels normalized in 89% of the zoledronic acid group compared with 58% of the risedronate group.

In a second follow-up study, patients who had had a 75% decrease in alkaline phosphatase or normalization of alkaline phosphatase were followed for another 18 months. The therapeutic response was maintained at the end of the 18 months in 98% of those treated with zoledronic acid, while only 57% of those treated with risedronate maintained the therapeutic response.

Zoledronic acid was approved for the treatment of osteoporosis several months after the initial approval for Paget's disease. It offers the advantage of once-yearly administration of the injection compared with the oncemonthly injection for osteoporosis with ibandronate sodium (Boniva).

The recent publication of significant data for the efficacy of zoledronic acid for osteoporosis includes a study of 3889 postmenopausal women with osteoporosis (N Engl J Med. 2007;356:1809-1822), which showed that once-yearly infusions of the drug for 3 years reduced the risk for morphometric vertebral fracture by 70%, the risk for hip fracture by 41%, and for nonvertebral fracture by 25%.

Treatment Considerations

Contraindications are hypocalcemia, hypersensitivity to the components of zoledronic acid, and pregnancy and lactation. As with all bisphosphonates, zoledronic acid should be avoided in patients with severe renal impairment (creatinine clearance <35 mL/min).

Because many patients with either Paget's disease or osteoporosis will be in their seventies or eighties, checking for renal function is necessary before initiating therapy with this agent. Thus, before beginning zoledronic acid therapy, physicians should check serum creatinine levels (to calculate glomerular filtration rate), as well as serum calcium and 25-hydroxyvitamin D levels.

Appropriate hydration, particularly in patients on diuretic therapy, is recommended before treatment onset to help prevent renal dysfunction.

Patients who are already receiving zoledronic acid as cancer therapy (Zometa) should not be given Reclast for Paget's disease or for osteoporosis.

Although no specific retreatment data are available, retreatment with zoledronic acid for either of these indications may be considered for patients who have relapsed (ie, based on an increase in serum alkaline phosphatase), or who have not achieved normal serum alkaline phosphatase levels.

Because zoledronic acid can induce hypocalcemia, all patients should also take supplemental calcium and vitamin D. Experts recommend 1500 mg of elemental calcium, taken every day in divided doses, plus at least 1000 U of vitamin D.

And because all bisphosphonates, including zoledronic acid, have been associated with osteonecrosis of the jaw, a dental examination and appropriate preventive dentistry are recommended before beginning treatment.

The most frequently reported adverse reactions are influenzalike illness and headache (11% each); dizziness, arthralgia, nausea, bone pain, pyrexia (9% each); and fatigue and rigors (8% each). Other side effects include lethargy, diarrhea, constipation, dyspepsia, and pain.

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