Zoledronic acid, an intravenous aminobisphosphonate that impairs the key metabolic pathways of mature osteoclasts and possibly stabilizes bone against resorption, and osteoprotegerin, a recombinant agent that inhibits osteoclastogenesis, are promising new therapies for the management of Paget's disease, according to research in the September 1, 2005, issue of The New England Journal of Medicine.
In the zoledronic acid (Aclasta®) study,1 357 patients with Paget's disease were assigned to receive either a 5 mg intravenous infusion of zoledronic acid over a 15-minute period followed by placebo tablets for 60 days, or a saline infusion followed by oral risedronate (30 mg/day) for 60 days. Additionally, all patients were given 1 g of calcium plus 400 to 1000 U vitamin D per day.
Zoledronic acid more convenient and faster-acting than risedronate
Patients given zoledronic acid exhibited a faster and more pronounced reduction in alkaline phosphatase levels than those receiving risedronate, the study showed. Measures of other biochemical markers of bone turnover also showed greater reductions with zoledronic acid than with risedronate.
Specifically, the rate of therapeutic response—defined as a 75% reduction in alkaline phosphatase levels—was consistently higher in the zoledronic acid group than the risedronate group, reaching 96% and 74.3%, respectively, at the conclusion of the 6-month trial (P <.001) .
Moreover, zoledronic acid appeared to be superior in terms of degree of disease suppression, rate of effect onset, and persistence of these effects beyond the 6-month trial period. The median time to first therapeutic response was 64 days among patients in the zoledronic acid arm versus 89 days for patients taking risedronate (P <.001).
While noting that bisphosphonates are good drugs for Paget's, Kenneth Lyles, MD, a professor of medicine at Duke University and the Veteran's Affairs Medical Center in Durham, North Carolina, points out that zoledronic acid is more convenient. "It's more convenient to take a shot over 15 minutes than take a bisphosphonate for 60 to 180 days straight," he tells CIAOMed. "This drug gets alkaline phosphatase levels faster and they stay down longer."
While the head-to-head study also illustrated that both zoledronic acid and risedronate improved pain, patients given zoledronic acid additionally showed improvement at 3 and 6 months in the ease of performing common daily activities. At 3 months, subjects receiving zoledronic acid were significantly better in this measure than those receiving risedronate.
Citing the importance of the study, Dr. Lyles says. "When [zoledronic acid] is approved by the FDA, the data on its effect on the activities of daily living suggest that it will be quite helpful." The US Food and Drug Administration issued an approvable letter for zoledronic acid in March 2005.
Adverse effects cited in the study indicated that Paget's patients who received zoledronic acid were twice as likely to suffer from a "flu-like" syndrome compared with subjects who received risedronate. Hypocalcemia can also occur with bisphosphonate treatment of Paget's disease; therefore, all subjects were instructed to take a calcium supplement.
Recombinant osteoprotegerin useful in juvenile Paget's
In a second study,2 two adult siblings with juvenile Paget's disease resulting from homozygous inactivating mutations in the gene encoding of osteoprotegerin were given a once-weekly subcutaneous injection (0.3–0.4 mg per kg of body weight) of recombinant osteoprotegerin. The treatment completely suppressed the high rate of bone resorption (assessed by N-telopeptide excretion) and also reduced bone formation.
After 15 months of treatment, radial bone mass increased in one patient by 9% and in the other by 30%, skeletal bisphosphonate retention decreased by 37% and 55%, respectively, and both showed radiographic improvement. Apart from mild hypocalcemia and hypophosphatemia, no apparent adverse events occurred, according to lead author Tim Cundy, MD, of the University of Auckland in Auckland, New Zealand.
"Our study provides corroborative evidence that the features of juvenile Paget's disease are indeed the result of osteoprotegerin deficiency and confirms the critical role of osteoprotegerin in regulating bone turnover in humans," Dr. Cundy and colleagues write. "[The study] constitutes a practical example of a genetic bone disease treated with replacement of an abnormal or missing protein."
New drugs also show promise for other hyper-resorptive bone diseases
In an editorial in the same issue as the new studies,3 L.J. Deftos, MD, JD, of the University of California at San Diego, writes that "[zoledronic acid and osteoprotegerin] have convenient dose regimens because of their long duration of action, a feature that should facilitate acceptance of these drugs among patients."
Historically, many of the drugs initially found to be effective in Paget's are ultimately used to treat osteoporosis and other bone diseases.
However, Dr. Deftos warns, "[The agents'] prolonged biologic effects, especially in the case of zoledronic acid, also raise a caution flag. Oversuppression of bone resorption and its deleterious consequences, such as the inhibition of skeletal metabolic activity and osteonecrosis, loom as even larger concerns with regard to these two agents than to shorter-acting drugs. The prudent and informed physician should anticipate these potential complications with the use of all potent antiresportive agents, especially bisphosphonates. Continued and careful studies should define the benefits and risks involved in treatment with these two agents and assign both of them to their proper place in the growing repertoire of bone-active drugs."
References
- Reid IR, Miller, P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease. N Engl J Med. 2005;353:898-908.
- Cundy T, Davidson J, Rutland MD, et al. Recombinant osteoprotegerin for juvenile Paget's disease. N Engl J Med. 2005;353:918-923.
- Deftos, LJ. Treatment of Paget's disease—taming the wild osteoclast. N Engl J Med.353:872-875.