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Pamidronate disodium, a second generation bisphosphonate, has been found to be safe as well as effective in the treatment of Paget’s disease of bone.1 It is licensed in the UK and many other countries for the intravenous treatment of Paget’s disease. Most units using pamidronate have found the occurrence of flu-like symptoms, fever, and myalgia in 20–30% of patients after the first pamidronate infusion.2 It therefore became our practice that patients received an initial 30 mg “test dose” of pamidronate before receiving a series of fortnightly infusions of 60 mg and this practice is now recommended by the manufacturers. This protocol however increases the number of infusions in a course of pamidronate treatment and therefore the cost and would only be justified if the adverse reactions were therefore minimised. We have therefore conducted a double blind placebo controlled trial to evaluate the need for this initial low dose “test” dose in patients receiving a course of 60 mg infusions.
Seventy four patients (40 female, 70.0 (9.4) years (mean (SD); 34 male, 67.5 (9.5) years) with mild to moderate Paget’s disease of bone (serum alkaline phosphatase (SAP) <500 IU/l, normal range <130 IU/l) who had never previously received pamidronate were recruited. Patients were randomised in a double blind fashion in to one of two arms A or B and all patients received a total of 210 mg pamidronate (Novartis Pharmaceuticals UK Ltd) in five fortnightly infusions as follows:
(A) Initial 30 mg infusion followed by three infusions of 60 mg pamidronate and a final placebo infusion at fortnightly intervals (n=41, mean SAP 202IU/l (range 85–450 IU/l).
(B) An initial placebo infusion followed by three infusions of 60 mg pamidronate and a final 30 mg pamidronate infusion at fortnightly intervals (n=33, mean SAP 191 IU/l (range 81–512 IU/l).
The frequency and severity of symptoms occurring after each infusion were assessed by questionnaire administered by one investigator (SJM). Unpaired Student’s t tests were used for statistical analysis.
The commonest symptoms complained of were headache, feeling hot and flushed, shivering and rigors, and each occurred in 20–30% of patients (table 1). These started within 48 hours of infusion and settled within 24 hours. All other symptoms were complained of by less than 5% of patients. There was increased reporting of adverse effects of symptoms in group A compared with group B after the first infusion (1.4 (1.0) versus 0.4 (0.2) (mean (SD)) symptoms, p <0.01, 30 mg pamidronate versus placebo). Likewise there were significantly more adverse effects in group B after the second infusion (60 mg pamidronate) than the first (placebo) (1.7 (1.1) versus 0.4 (0.1), p <0.01). In group A there was a decrease in symptoms between the first (1.4) and second (1.0) infusions (30 mg versus 60 mg pamidronate) despite a larger dose of pamidronate being given in the second infusion. In both groups the maximum number of symptoms occurred after the first pamidronate infusion and was similar whether the first exposure to pamidronate was 30 mg or 60 mg. In both groups the number of reported symptoms decreased thereafter and there was no significant difference between symptoms reported in the two groups after the third, fourth or fifth infusion.
This study confirms previous findings that 20–30% of patients suffer transient symptoms related to pamidronate infusion.2 3 In this study we found that 20–30% of patients who had never previously received pamidronate treatment suffered symptoms of feeling hot and flushed, shivering and headaches within 48 hours of their first pamidronate infusion and this lasted for less than 24 hours.
An acute febrile response and haematological changes had been reported after pamidronate infusion.4-6 Therefore it is likely that the symptoms in our study are similarly related to an acute febrile response to pamidronate infusion.
We found that these symptoms occurred irrespective of whether the dose of pamidronate administered was 30 mg or 60 mg. We therefore suggest that patients with mild-moderate Paget’s disease of bone are treated with three infusions of 60 mg without any need for initial low dose “test” dose thereby reducing the cost of treatment and the inconvenience and number of visits to the hospital for the patient.
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