Elsevier

Bone

Volume 34, Issue 4, April 2004, Pages 747-754
Bone

A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone

https://doi.org/10.1016/j.bone.2003.12.011Get rights and content

Abstract

Second and third generation bisphosphonates are the treatment of choice for Paget’s disease of bone. These drugs are more effective than calcitonin and etidronate, but there have been no head to head, randomized controlled trials comparing potent bisphosphonates. We conducted a 2-year, randomized, open-label trial comparing oral alendronate and intravenous pamidronate in 72 subjects with Paget’s disease. Randomization was stratified according to baseline plasma total alkaline phosphatase (ALP) and previous bisphosphonate treatment (yes or no). All previously treated patients had received pamidronate but not alendronate. Assigned treatments were pamidronate (60 mg) every 3 months as a single infusion or alendronate (40 mg) daily in 3-month blocks, continued until biochemical remission (defined as both ALP and urine deoxypyridinoline (DPD)/creatinine ratio in the reference range) or a clear plateau effect was observed. At 1 year, nonresponders to pamidronate were crossed over to alendronate treatment. At 1 year, 31/36 (86%) subjects randomized to alendronate achieved biochemical remission compared with 21/36 (56%) for pamidronate (P = 0.017). There was a significantly greater reduction in ALP (P < 0.001) and DPD/creatinine ratio (P < 0.001) for alendronate compared with pamidronate treatment. In previously untreated patients, alendronate resulted in remission in 20/22 (91%) subjects compared with 19/22 (86%) of pamidronate-treated subjects, which was not significantly different; however, alendronate resulted in a significantly greater reduction in ALP (P = 0.014) and DPD/creatinine ratio (P < 0.001). In previously treated patients, alendronate resulted in remission in 11/14 (79%) subjects compared with 2/14 (14%) for pamidronate (P < 0.001), with a significantly (P < 0.001) greater reduction in both ALP and DPD/creatinine ratio. Of subjects crossed over from pamidronate to alendronate, 10/14 (71%) achieved remission, including 9/11 (82%) previously treated patients. We conclude that, in patients with previously untreated Paget’s disease of bone, alendronate and pamidronate have similar efficacy in achieving biochemical remission. In patients previously treated with pamidronate, alendronate is more effective.

Introduction

Paget’s disease is a chronic, progressive disorder of bone characterized by focal areas of excessive osteoclastic resorption accompanied by a secondary increase in osteoblastic activity [1]. This results in bone expansion, structural weakness, and deformity. Calcitonin and the first generation bisphosphonate etidronate were widely used to treat the disorder, but have largely been superseded by potent second and third generation bisphosphonates such as pamidronate, alendronate, and risedronate [1], [2], [3]. These drugs are more effective than calcitonin or etidronate [3], [4], [5], [6], [7] and are now regarded as the treatments of choice [1], [2], [3]. There have been no randomized clinical trials comparing two or more second or third generation bisphosphonates in a head to head fashion, and it is not known if these drugs differ in therapeutic efficacy. We conducted a randomized clinical trial comparing intravenous pamidronate and oral alendronate sodium for the treatment of Paget’s disease of bone. Preliminary data from some subjects were published previously in a paper examining resistance to bisphosphonate treatment [8]. In this paper, we report the final results of the study.

Section snippets

Study design, subjects, and treatments

The trial was an investigator-initiated study with a randomized, open-label, parallel design conducted in three centers in Western Australia. Patient eligibility was based on the presence of typical lesions of Paget’s disease on isotope bone scanning and radiographs and plasma total alkaline phosphatase (ALP) concentration above the upper limit of the laboratory reference range (135 U/l). Subjects previously treated for Paget’s disease were eligible only if at least 3 months had elapsed since

Baseline characteristics, patient disposition, and treatments

Recruitment began in May 1997, and the study was completed in October 2001. A flowchart of patient disposition is shown in Fig. 1. Seventy-two subjects were recruited to the study, of whom 36 were randomized to alendronate and 36 to pamidronate. Slow recruitment towards the end of the study led to a decision to halt recruitment at 72 subjects, rather than 80 as originally planned. Fifty-nine patients (82%) completed the 2-year study, comprising 31 in the alendronate group and 28 in the

Discussion

In this study, the first randomized controlled trial of two potent bisphosphonates for the treatment of Paget's disease, oral alendronate had superior efficacy compared with intravenous pamidronate. A significantly greater proportion of subjects assigned to alendronate treatment achieved full biochemical remission compared with pamidronate, and there was a significantly greater reduction in bone turnover in the alendronate group. There was, however, a major difference in treatment response

Acknowledgements

This work was supported by research grants from Merck, Sharp & Dohme (Australia), Novartis Pharmaceuticals Australia, and the Arthritis Foundation of Western Australia.

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