Siris 1996.

Methods	RCT: Randomisation ratio: 1:1 (alendronate 40 mg: etidronate 400 mg). Superiority design
Participants	Diagnostic criteria: Paget's disease of bone was confirmed by standard clinical, radiological or scintigraphic imaging or both methods Inclusion criteria: Serum alkaline phosphatase at least twice the ULN if the participant had never been treated with bisphosphonates or plicamycin, or at least 4 times the ULN if the participant had received such therapy at any time in the past. Exclusion criteria: treatment with any bisphosphonates or plicamycin within 12 months or calcitonin within 3 months preceding screening; osteolytic Pagetic lesion of a weight‐bearing bone that may be a contra‐indication for etidronate therapy; use of medications that might affect bone metabolism; associated health problems that could affect participation in the study or interfere with interpretation of the data, including active upper gastrointestinal, genitourinary, cardiovascular, liver, kidney or pulmonary disease. Number screened: Not stated. Number randomised: 89. Number analysed: 88 (69 years, 67% male, percentages of monostotic and symptomatic participants not stated, 25% previously treated for Paget's disease of bone)
Interventions	Two parallel treatment groups: alendronate 40 mg (1 x etidronate placebo tablet and 1 x 40 mg alendronate tablet for 6 months) and etidronate 400 mg (1 x 400 mg etidronate tablet and 1 x alendronate placebo tablet for 6 months). Co‐interventions: All participants received daily vitamin supplements containing 450 mg calcium carbonate and 400 IU vitamin D. Analgesics were available on demand and use was not balanced ("the regression analysis with adjustment for analgesics use at month 6 between the two treatment groups approached significance")
Outcomes	Outcomes reported in abstract Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity. Secondary endpoints: mean percentage change from baseline in pain (measured using Brief Pain Inventory slightly modified for use in Paget's disease of bone); adverse events related to use of bisphosphonates; withdrawal due to adverse events; participants who normalised alkaline phosphatase level. Time points for measurement: Baseline, 1 month, 3 months, 6 months. How were the outcomes measured: prospectively
Setting and date	11 centres in USA. Period when the study was conducted: Not reported
Follow up period	6 months
Publication details and funding source	Language of publication: English. Publication status: peer‐reviewed journal; full article. Funding source: Not reported. Declarations of interest among primary researchers: Not reported
Notes	Transiliac bone biopsy was conducted for 43 participants at month 6. Bone biopsies were obtained from 25 healthy volunteers as control
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "the study was randomised". Comment: insufficient information provided to permit judgement. Allocation was probably centralized because this was a multicentre study
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The study was randomised and double blind", "The etidronate tablets were purchased as Didronel, crushed, and recompressed into tablets identical to placebo for etidronate". Comment: Probably done.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Baseline and 6 months radiographs of one or more sites were read by one radiologist, who remained blind with respect to both treatment allocation and sequence of films". "Each specimen (bone biopsy) was blinded, so that the reader was unaware of the subjects' drug therapy."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: Only one participant was excluded from the analysis (in the alendronate group). Reason for exclusion was reported. The proportion of missing outcomes compared with observed event risk was insufficient to have a relevant impact of the effect estimate
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	There were differences between groups in co‐interventions because analgesics were taken on demand and use was not balanced. However this was thought unlikely to have resulted in bias. No other risks of bias found, but reporting was insufficient to permit judgement