Paget's Disease and Bisphosphonates
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《新英格兰医药杂志》
To the Editor: Reid et al. (Sept. 1 issue)1 compare a single infusion of 5 mg of zoledronic acid with 30 mg per day of oral risedronate for 60 days, showing the advantage of zoledronic acid over risedronate in the treatment of Paget's disease. Previously, Reid et al. reported on the efficacy and safety of oral alendronate at a dose of 40 mg per day.2 Others have shown that oral alendronate at 40 mg per day was effective but associated with side effects.3,4 However, considerable improvement in biochemical markers was shown even with 5 mg of oral alendronate per day.5 In my experience, the once-weekly preparation of alendronate (70 mg) appears to be very effective in controlling the laboratory and clinical manifestations of Paget's disease. From an economic perspective (data from ePocrates, a handheld-based drug reference), intravenous zoledronate (5 mg every 6 months) would cost $920 (for the drug alone), risedronate (30 mg for 60 days every 6 months) would cost $1,020, and once-weekly alendronate would cost $420 (for a full 6-month regimen, although considerably shorter courses are usually required).
While a formal evaluation of alendronate for the treatment of Paget's disease is performed, the weekly alendronate formulation, which is well tolerated in patients with osteoporosis, provides a reasonable, convenient, and cost-effective option.
Yair Liel, M.D.
Soroka University Medical Center
84101 Beer-Sheva, Israel
liel@bgu.ac.il
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.
Reid IR, Nicholson GC, Weinstein RS, et al. Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med 1996;101:341-348.
Adami S, Mian M, Gatti P, et al. Effects of two oral doses of alendronate in the treatment of Paget's disease of bone. Bone 1994;15:415-417.
Walsh JP, Ward LC, Stewart GO, et al. A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone. Bone 2004;34:747-754.
Takada J, Iba K, Yamashita T. Low dose of oral alendronate decreases bone turnover in Japanese patients with Paget's disease of bone. J Bone Miner Metab 2005;23:333-336.
To the Editor: Bisphosphonates represent a major advance in the management of Paget's disease of bone. Serum levels of alkaline phosphatase are used to evaluate disease activity and the response to therapy.1 Reid et al. report that the efficacy of zoledronic acid in achieving remission of Paget's disease (defined as an alkaline phosphatase level within the normal range) is higher than that of risedronate.2 We previously reported the efficacy of risedronate (30 mg per day for eight weeks, with repeated treatment at the same dosage in patients without disease remission at day 120) in 15 patients with severe and clodronate-resistant Paget's disease. By day 360, 13 patients had had a remission (after one course of risedronate for 9 patients and after two courses for 4 patients), and 2 patients had a significant decrease in alkaline phosphatase levels without remission.3 After three years, none of the patients had evidence of relapse, defined as a consistent and progressive increase in alkaline phosphatase levels from the nadir values (Figure 1). The adopted therapeutic protocol seems to be able to prevent the progression of Paget's disease.
Figure 1. Serum Levels of Total Alkaline Phosphatase in Patients Receiving Risedronate.
Risedronate was administered orally to 15 patients with severe and clodronate-resistant Paget's disease at a daily dose of 30 mg for eight weeks. The treatment was repeated, at the same dosage, in six patients (dotted lines) whose serum total alkaline phosphatase activity did not normalize at 120 days.
Domenico Rendina, M.D.
Federico II University
80131 Naples, Italy
Gianpaolo De Filippo, M.D.
Gaetano Rummo Hospital
82100 Benevento, Italy
Giuseppe Mossetti, M.D.
Federico II University
80131 Naples, Italy
giumosse@unina.it
References
Siris ES. Goals of treatment for Paget's disease of bone. J Bone Miner Res 1999;14:Suppl 2:49-52.
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.
Rendina D, Mossetti G, Viceconti R, Sorrentino M, Nunziata V. Risedronate and pamidronate treatment in the clinical management of patients with severe Paget's disease of bone and acquired resistance to bisphosphonates. Calcif Tissue Int 2004;75:189-196.
The authors reply: Dr. Liel suggests that Paget's disease can be adequately treated with smaller doses of bisphosphonates than are conventionally used. This view may be correct, but efficacy depends on a number of factors, including disease severity and the end point chosen to define adequacy of treatment. It is a common observation that mild elevations in markers of bone turnover can be normalized with moderate doses of bisphosphonates. This does not necessarily mean that disease activity has been arrested, and it is quite clear that positive bone scintigraphy with progression of radiologic lytic lesions can occur in this context.1 Substantially larger doses of bisphosphonate may be needed to produce healing of such lytic lesions and sometimes to relieve bone pain. Therefore, in clinical practice it is important to define the therapeutic end point for each patient and to provide treatment that is adequate to achieve it. Cost-effectiveness will be determined, in part, by the extent and duration of any reduction in disease activity. In our view, Dr. Liel's projected costs for various treatments for this condition are inappropriate, since there is no suggestion that zoledronate needs to be repeated every six months in Paget's disease. On the contrary, our study suggests that repeated administration may not be necessary for some years, since less than 1 percent of patients had relapsed after two years of follow-up.
Dr. Rendina and colleagues report a 60 percent rate of biochemical remission with two months' treatment with risedronate, increasing to 87 percent when two courses of this drug are administered. This is broadly consistent with the findings of our own study and also agrees with our previous suggestion that patients with more severe disease will often require larger doses of bisphosphonate. The low incidence of relapse among the patients of Rendina et al. who were treated with risedronate is at variance with our own findings but may be attributable to the fact that the more severely affected patients in their cohort were given two courses of therapy. The advantage of zoledronic acid is that a sustained remission can be achieved after a single 15-minute infusion, which is much more convenient for patients than either two-month or four-month courses of tablets. However, comparisons between treatments with the use of case series are problematic, since only randomization can provide true comparability of baseline status.
Ian R. Reid, M.D.
University of Auckland
Auckland, New Zealand
i.reid@auckland.ac.nz
Paul Miller, M.D.
Colorado Center for Bone Research
Lakewood, CO 80227
David Hosking, M.D.
Nottingham City Hospital
Nottingham NG5 1PB, United Kingdom
References
Ibbertson HK. Paget's disease of bone. In: Nordin BEC, Need AG, Morris HA, eds. Metabolic bone and stone disease. 3rd ed. Edinburgh, Scotland: Churchill Livingstone, 1993:181-212.
While a formal evaluation of alendronate for the treatment of Paget's disease is performed, the weekly alendronate formulation, which is well tolerated in patients with osteoporosis, provides a reasonable, convenient, and cost-effective option.
Yair Liel, M.D.
Soroka University Medical Center
84101 Beer-Sheva, Israel
liel@bgu.ac.il
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.
Reid IR, Nicholson GC, Weinstein RS, et al. Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med 1996;101:341-348.
Adami S, Mian M, Gatti P, et al. Effects of two oral doses of alendronate in the treatment of Paget's disease of bone. Bone 1994;15:415-417.
Walsh JP, Ward LC, Stewart GO, et al. A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone. Bone 2004;34:747-754.
Takada J, Iba K, Yamashita T. Low dose of oral alendronate decreases bone turnover in Japanese patients with Paget's disease of bone. J Bone Miner Metab 2005;23:333-336.
To the Editor: Bisphosphonates represent a major advance in the management of Paget's disease of bone. Serum levels of alkaline phosphatase are used to evaluate disease activity and the response to therapy.1 Reid et al. report that the efficacy of zoledronic acid in achieving remission of Paget's disease (defined as an alkaline phosphatase level within the normal range) is higher than that of risedronate.2 We previously reported the efficacy of risedronate (30 mg per day for eight weeks, with repeated treatment at the same dosage in patients without disease remission at day 120) in 15 patients with severe and clodronate-resistant Paget's disease. By day 360, 13 patients had had a remission (after one course of risedronate for 9 patients and after two courses for 4 patients), and 2 patients had a significant decrease in alkaline phosphatase levels without remission.3 After three years, none of the patients had evidence of relapse, defined as a consistent and progressive increase in alkaline phosphatase levels from the nadir values (Figure 1). The adopted therapeutic protocol seems to be able to prevent the progression of Paget's disease.
Figure 1. Serum Levels of Total Alkaline Phosphatase in Patients Receiving Risedronate.
Risedronate was administered orally to 15 patients with severe and clodronate-resistant Paget's disease at a daily dose of 30 mg for eight weeks. The treatment was repeated, at the same dosage, in six patients (dotted lines) whose serum total alkaline phosphatase activity did not normalize at 120 days.
Domenico Rendina, M.D.
Federico II University
80131 Naples, Italy
Gianpaolo De Filippo, M.D.
Gaetano Rummo Hospital
82100 Benevento, Italy
Giuseppe Mossetti, M.D.
Federico II University
80131 Naples, Italy
giumosse@unina.it
References
Siris ES. Goals of treatment for Paget's disease of bone. J Bone Miner Res 1999;14:Suppl 2:49-52.
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.
Rendina D, Mossetti G, Viceconti R, Sorrentino M, Nunziata V. Risedronate and pamidronate treatment in the clinical management of patients with severe Paget's disease of bone and acquired resistance to bisphosphonates. Calcif Tissue Int 2004;75:189-196.
The authors reply: Dr. Liel suggests that Paget's disease can be adequately treated with smaller doses of bisphosphonates than are conventionally used. This view may be correct, but efficacy depends on a number of factors, including disease severity and the end point chosen to define adequacy of treatment. It is a common observation that mild elevations in markers of bone turnover can be normalized with moderate doses of bisphosphonates. This does not necessarily mean that disease activity has been arrested, and it is quite clear that positive bone scintigraphy with progression of radiologic lytic lesions can occur in this context.1 Substantially larger doses of bisphosphonate may be needed to produce healing of such lytic lesions and sometimes to relieve bone pain. Therefore, in clinical practice it is important to define the therapeutic end point for each patient and to provide treatment that is adequate to achieve it. Cost-effectiveness will be determined, in part, by the extent and duration of any reduction in disease activity. In our view, Dr. Liel's projected costs for various treatments for this condition are inappropriate, since there is no suggestion that zoledronate needs to be repeated every six months in Paget's disease. On the contrary, our study suggests that repeated administration may not be necessary for some years, since less than 1 percent of patients had relapsed after two years of follow-up.
Dr. Rendina and colleagues report a 60 percent rate of biochemical remission with two months' treatment with risedronate, increasing to 87 percent when two courses of this drug are administered. This is broadly consistent with the findings of our own study and also agrees with our previous suggestion that patients with more severe disease will often require larger doses of bisphosphonate. The low incidence of relapse among the patients of Rendina et al. who were treated with risedronate is at variance with our own findings but may be attributable to the fact that the more severely affected patients in their cohort were given two courses of therapy. The advantage of zoledronic acid is that a sustained remission can be achieved after a single 15-minute infusion, which is much more convenient for patients than either two-month or four-month courses of tablets. However, comparisons between treatments with the use of case series are problematic, since only randomization can provide true comparability of baseline status.
Ian R. Reid, M.D.
University of Auckland
Auckland, New Zealand
i.reid@auckland.ac.nz
Paul Miller, M.D.
Colorado Center for Bone Research
Lakewood, CO 80227
David Hosking, M.D.
Nottingham City Hospital
Nottingham NG5 1PB, United Kingdom
References
Ibbertson HK. Paget's disease of bone. In: Nordin BEC, Need AG, Morris HA, eds. Metabolic bone and stone disease. 3rd ed. Edinburgh, Scotland: Churchill Livingstone, 1993:181-212.