Published: Aug. 31, 2005
Updated: Sept. 1, 2005
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By Duke Medicine News and Communications
DURHAM, N.C. -- An international team of researchers has found that zoledronic acid, a drug that reduces bone resorption, appears to improve the response rate and duration of remission in people with Paget's disease -- a painful, debilitating chronic bone disease that usually affects people over 60 years of age. The study results appear in the Sept. 1, 2005, issue of the New England Journal of Medicine.
"I'm enthusiastic that we have found a treatment that works quickly, controls the disease better and lasts longer than other treatments we've been using," said Kenneth W. Lyles, MD, a professor of medicine in the geriatrics division at Duke University and Durham Veterans Affairs Medical Centers. "This is not a disease that we can cure, but it is a disease that we manage by using appropriate medications."
The study compared a single intravenous dose of zoledronic acid, an aminobisphosphonate, to a 60 day oral dose of risedronate, an oral bisphosphonate approved by the Food and Drug Administration (FDA) for treatment of Paget's disease. Bisphosphonates have been used to treat this disorder since the 1970s. They are also used to treat other skeletal diseases, such as osteoporosis. The drugs are also used to treat patients with certain types of cancer including breast, multiple myeloma and prostate, to prevent or control the spread of cancer to bone.
Paget's disease of bone is a chronic skeletal disease characterized by an excessive resorption, or breakdown, of bone and subsequent abnormal formation of bone tissue that, over time, causes affected bones to weaken. People with the disease experience problems that can include localized bone pain, misshapen or enlarged bones, fractures and bowing of limbs and certain affected patients can suffer disability. It is the second most common skeletal remodeling disease in the world, according to the National Institutes of Health, affecting about one million people in the U.S.
Oral bisphosphonates can be inconvenient for patients to take. They must be taken with water while fasting and patients need to wait 30 to 60 minutes before taking other medications or food. In addition, the oral bisphosphonates can cause esophageal irritation, so patients are asked to sit or stand for 30 minutes after taking their drug.
"Intravenous zoledronic acid could offer greater convenience to patients and may improve their compliance with treatment," Lyles added.
Researchers enrolled 357 people into the clinical trial at 76 centers located throughout the U.S. and in nine other countries. Those enrolled were 30 years of age or older and had confirmed Paget's disease of bone. Participants in the six-month clinical trial were randomly assigned in a double-blind fashion to receive either a 5-milligram intravenous infusion of zoledronic acid (182 patients) over a 15-minute period followed by placebo tablets for 60 days, or to receive a saline infusion followed by a 30 milligram tablet of risedronate (175 patients) per day for 60 days. Additionally, all patients were given one gram of calcium plus 400 to 1000 units of a vitamin D supplement per day.
Blood tests were performed to measure levels of the enzyme alkaline phosphatase, a marker of disease activity. Patients given zoledronic acid had faster and more pronounced reduction of alkaline phosphatase levels than did their counterparts who received risedronate. Measures of other biochemical markers of bone turnover showed greater reductions with zoledronic acid than with risedronate.
According to the research team, the rate of therapeutic response -- defined as a 75 percent reduction in alkaline phosphatase levels -- was consistently higher in the zoledronic acid group than in the risedronate group, reaching 96 percent and 74.3 percent respectively, at the six month trial conclusion. Zoledronic acid appeared to be superior in terms of the degree of disease suppression, the rate of effect onset, and – according to data collected by the team -- the persistence of these effects beyond the six-month trial period.
"It is important to note that risedronate is a good drug and helps a number of people with Paget's disease," said Lyles. "We're impressed with zoledronic acid in terms of how quickly it works and how long it appears to last, as well as how much easier it can be for a patient to take. It could help more people adhere better to their treatment regimen."
Lyles pointed out that the intravenous zoledronic acid was not without side-effects. Ten to forty percent of patients who receive bisphosphonates for Paget's disease of bone can develop a flu-like syndrome within three to five days of starting the medication. The patient can have muscle aches, fever and bone pain. In this study, subjects who received zoledronic acid were twice as likely to have the "flu-like" syndrome as subjects who received risedronate. Hypocalcemia can occur with bisphosphonate treatment of Paget's disease so all subjects were instructed to take a calcium supplement.
In this study both zoledronic acid and risedronate improved the pain of study participants. A measurement of ease of performing common activities of daily living showed zoledronic acid improved a measure of the ability to perform such activities at three and six months. At three months, this measure showed that subjects who received zoledronic acid were significantly better than those who received risedronate.
This study was supported by a research grant from Novartis Pharma AG, Basel, Switzerland, which market zoledronic acid for the treatment of Paget's disease of bone when approved by the FDA. Lyles has served as a paid advisor to Novartis regarding zoledronic acid for treating Paget's disease and osteoporosis. He has received funding from Novartis to lecture to physicians about zoledronic acid and Paget's disease. He is also an inventor on a use patent for the use of zoledronic acid in prevention of subsequent fractures after a hip fracture.
Other authors on the study include Ian Reid, MD, University of Auckland; Paul Miller, MD, the Colorado Center for Bone Research; William Fraser, MD, Royal Liverpool University Hospital, Liverpool, UK; Jacques Brown, MD, Le Centre Hospitalier Universitaire de Quebec, Sainte-Foy, Quebec, Canada; Youssef Saidi, Ph.D., Novartis Pharma, Besel, Switzerland; Peter Mesenbrink, Ph.D., Guoqin Su, Ph.D., Judy Pak, Ken Zelenakas, Monica Luchi, MD, and Peter Richardson, of Novartis Pharmaceuticals, East Hanover, NJ; and David Hosking, MD, Nottingham City Hospital, Nottingham, UK.