Walsh 2004.

Methods	RCT. Randomisation ratio: 1:1 (alendronate 40 mg: pamidronate 60 mg). Superiority design
Participants	Diagnostic criteria: Paget's disease of bone was confirmed by the presence of typical lesions of Paget’s disease on isotope bone scanning and radiographs. Inclusion criteria: Serum alkaline phosphatase above the upper limit of laboratory reference range. Exclusion criteria: participants previously treated were excluded if < 3 months had elapsed since calcitonin treatment or < 6 months since bisphosphonate treatment, and if Paget’s disease of bone was in biochemical relapse, defined as plasma total alkaline phosphatase > 135 µ/L and at least 50% higher than the nadir value during previous treatment accompanied by radiological relapse of previously demonstrated lytic lesions. major comorbidity, untreated vitamin D deficiency, primary hyperparathyroidism, metabolic bone disease other than uncomplicated osteoporosis, recent partial or complete fracture through pagetic bone, clinically significant upper gastrointestinal disease, liver disease, and kidney impairment (plasma creatinine > 150 Amol/L). Number screened: 139. Number randomised: 72. Number analysed: 72 (70 years, 58% male, % monostotic not stated, 94% symptomatic participants, 39% participants previously treated for Paget's disease of bone)
Interventions	Two parallel treatment groups: alendronate 40 mg daily in 3 months blocks and pamidronate four x 60 mg IV infusions a year (once every 3 months). Treatment was continued until biochemical remission was achieved or there were a no significant reduction on two consecutives measurements. Biochemical remission was defined as both, serum total alkaline phosphatase activity and urine deoxypyridinoline/creatinine ratio within the reference range. Co‐interventions: All participants with plasma baseline total alkaline phosphatase > 675 U/L were prescribed ergocalciferol 30,000 U weekly for 3 months and calcium carbonate 600 mg daily for 8 months to minimize bisphosphonate‐induced secondary hyperparathyroidism. Other participants were treated with calcium and vitamin D supplements at the treating clinician’s discretion
Outcomes	Outcomes reported in abstract: Primary endpoint: Proportion of participants achieving biochemical remission (see above). Secondary endpoints: Numbers of participants; with change in bone pain (measured on VAS); with change on quality of life from baseline (assessed using the SF‐36 Australian version); who experienced severe side effects related to use of bisphosphonates; who withdrew due to adverse events, mean percentage change from baseline in serum total alkaline phosphatase activity; who normalised alkaline phosphatase level; and who relapsed due to recurrence of increased serum alkaline phosphatase level. Time points for measurement: Baseline, 3, 6, 9, 12, 18 and 24 months. How were the outcome measured: Prospectively
Setting and date	Three centres in Western Australia. Period when the study was conducted: From May 1997 to October 2001
Follow up period	1 year without protocol amendment (2 year with protocol amendment)
Publication details and funding source	Language of publication: English. Publication status: peer‐reviewed journal; full article. Funding source: Although the authors described the trial as an "investigator‐initiated study", the study was supported by research grants from Merck, Sharp & Dohme (Australia), Novartis Pharmaceuticals Australia and the Arthritis Foundation of Western Australia. Declarations of interest among primary researchers: Not stated
Notes	The initial protocol was amended to cross participants over from pamidronate to alendronate treatment at 12 months. According to the author, it was apparent that some participants randomised to pamidronate were showing little or no biochemical response to treatment and for "ethical" reasons, they amended the protocol so that participants randomised to pamidronate who did not achieve biochemical remission at 12 months were crossed over to alendronate treatment for the second year of the study. We included data from the first year only in the meta‐analysis.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "To ensure that the two treatment groups were well matched, randomisation was stratified (using an in‐house computer program) by two variables: baseline plasma alkaline phosphatase (in three strata: 136–270, 271–675, > 675 U/L) and previous bisphosphonate treatment (as a binary variable: yes or no)." "In the course of the study, it was apparent that some patients randomised to pamidronate (predominantly in the previously treated subgroup) were showing little or no biochemical response to treatment. For ethical reasons, the protocol was amended so that patients randomised to pamidronate who did not achieve biochemical remission at 12 months were crossed over to alendronate treatment for the second year of the study". Comment: The risk assessment was judged as low risk for first year data. For the second year, allocation was broken, and the risk of bias was assessed as high
Allocation concealment (selection bias)	Low risk	Authors describe using a computer program to generate the allocation
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open label trial
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open label trial
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Proportions of patients achieving remission for each treatment (on an intention to treat basis) were compared by Fisher’s exact test". Comment: Data on screened participants, randomised participants and withdrawals (with reasons) are reported in a flow chart (Figure 1)
Selective reporting (reporting bias)	Unclear risk	Methods and results sections were consistent. Insufficient information to permit judgement. We did not have access to a trial register record or study protocol to know if there was a prespecified record of the studies outcomes
Other bias	Unclear risk	Likely high at 12 months due to amendment of the initial protocol. No other risks of bias found, but reporting was insufficient to permit judgement

Abbreviations: IV ‐ intravenous; RCT ‐ randomised controlled trial; ULN ‐ upper limit of normal