Joseph R.
Tucci, MD

The first new treatment for Paget's disease of bone to be approved in almost 10 years is as effective as standard treatments but offers advantage in terms of ease of use. This IV bisphosphonate, zoledronic acid (Reclast; Novartis), is the first therapy that can be given as a single-dose infusion, 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).

Zoledronic acid is more effective, has a faster onset of action, and is more likely to induce remission than oral risedronate sodium (Actonel). In addition, 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.

"What's exciting about zoledronic acid is that it's given as a 15-minute infusion, and just once. That would seem to be more acceptable for many patients," Joseph R. Tucci, MD, told IMWR.

Disease Characteristics

Paget's disease is the second most common metabolic disease of bone, after osteoporosis. "It is a strange disease in that it can affect only 1 or 2 bones or multiple bones. There's no good explanation for this," said Dr Tucci, chief, Division of Endocrinology, Roger Williams Medical Center, Providence, RI.

The disease occurs primarily in patients aged >45 or 50 years; about 1 million patients over the age of 65 in the United States have the disease.

In addition to bone pain and skeletal deformities, such as bowed arms and legs or an enlarged head, complications can include arthritis, neurologic manifestations (hearing loss, spinal stenosis), fractures and malunion, and on rare occasions osteosarcoma.

Of the 2 major cellular elements in bone, Paget's disease involves what Dr Tucci refers to as "the Pac Man of bone, the osteoclast." The major culprit is indeed 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 that lay down bone that is ultimately structurally abnormal and weaker than nonpagetic bone.

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, or on radiographic findings.

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 vs 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.

The drug is not yet approved for the treatment of osteoporosis, but Dr Tucci said, "I can only assume that soon we'll be hearing about possible approval of zoledronic acid for this indication."

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

Treatment Considerations

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.

"If a patient is asymptomatic, but there is an area of critical involvement such as a long bone or weight-bearing bone, one should not wait until the patient becomes symptomatic. Intervene with treatment," Dr Tucci says.

Zoledronic acid is indicated for patients with active Paget's disease, those who are symptomatic, or for those who are at risk for disease complications with the goal of reducing serum alkaline phosphatase levels or even producing remission (ie, normalization of alkaline phosphatase levels).

Contraindications are hypocalcemia and, as with all bisphosphonates, severe renal impairment (creatinine clearance <35 mL/min).

"The problem is that very often, we're dealing with patients with Paget's disease who are in their 70s, 80s, and even their 90s. With age, renal function gradually decreases. Accordingly, renal function must be assessed," Dr Tucci stresses.

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.

Zoledronic acid for Paget's disease should be given as a 5-mg single-dose infusion over at least 15 minutes in 100 mL of water. Although no specific retreatment data are available, retreatment 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.

Since zoledronic acid can induce hypocalcemia, all patients should take supplemental calcium and vitamin D. "We routinely recommend 1500 mg of elemental calcium, each and every day in divided doses, and, at a minimum, about 1000 IU of vitamin D per day," Dr Tucci said.

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.

NOTE: Oral bisphosphonates are taken with 6-8 oz of water; these agents are associated with an increased risk for osteonecrosis of the jaw.
GI = gastrointestinal; GFR = glomerular filtration rate; IM = intramuscular.