Reginster 1992.

Methods	RCT. Randomisation ratio: 1:1:1:1:1 (placebo: tiludronate 100 mg: tiludronate 200 mg: tiludronate 400 mg: tiludronate 800 mg). Superiority design
Participants	Diagnostic criteria: Paget's disease of bone with characteristic radiologic lesions and/or with 99mTc bisphosphonates scintigraphic evidence of local increase in bone turnover. Inclusion criteria: Serum alkaline phosphatase levels were at least twice the ULN. Exclusion criteria: free of kidney, liver, neurologic, haematologic, inflammatory and immune disorders. taking no medications known to interfere with bone metabolism. Different minimal washout periods prior to the study were established for bone drugs: 6 months for etidronate, 2 months for calcitonin, 2 years for tiludronate and 2 years for clodronate. Number screened: not stated. Number randomised: 149. Number analysed: 149 (69 years, 54 % male, % monostotic not stated, % symptomatic participants not stated, 82% previously treated for Paget's disease of bone)
Interventions	The study was divided into 2 periods. In the first period there were five parallel treatment groups: placebo (4 x placebo capsules), tiludronate 100 mg (2 x placebo and 2 x 50 mg tiludronate capsules), tiludronate 200 mg (4 x capsules 50 mg tiludronate), tiludronate 400 mg (4 x capsules 100 mg), tiludronate 800 mg (4 x capsules 200 mg tiludronate). All participants took 2 capsules at 10.00 am and 2 capsules at 4.00 pm daily for 3 months. In the second period all participants received 4 placebo capsules. The investigators initiated tiludronate therapy during the second period for participants experiencing a lack of efficacy (participants were considered discontinued from the study). Co‐interventions: Not reported
Outcomes	Outcomes reported in abstract Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity. Secondary endpoints: change in bone pain (Huskisson VAS; range 0 cm (no pain) to 10 cm (maximal pain). A pain index was derived from pain severity and time course scores. Only pain in bones or joints in which Pagetic lesions had been clearly demonstrated by radiography or bone scans were considered. For each painful bone or joint, the participant rated pain severity (mild = 1, moderate = 2, severe = 3) and time course (on motion = 1, intermittent = 2, constant = 3). By multiplying the scores for severity and time course, a pain index was calculated for each site. The scores for all sites were added to yield an overall pain index; adverse events related to use of bisphosphonates; withdrawal due to adverse events; and achieved normalised alkaline phosphatase level. Time points for measurement: Baseline and monthly intervals. How were the outcomes measured: prospectively
Setting and date	29 centres in Belgium, France and USA. Period when the study was conducted: Not stated
Follow up period	6 months
Publication details and funding source	Language of publication: English Publication status: peer‐reviewed journal; full article. Funding source: Supported by Sanofi Research, Montpellier, France. Declarations of interest among primary researchers: Not stated
Notes	Data on tiludronate groups were pooled for meta‐analysis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "double‐blind, randomised, placebo‐controlled study". Comment: Insufficient information provided to permit judgement, but probably low risk because the allocation process should have been centralized because the study involved 29 centres in different countries
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "double‐blind, randomised, placebo‐controlled study". Comment: Probably done.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "All biochemical determinations were performed at a central location throughout the period of study." Comment: Insufficient information provided, but likely low risk because it is unlikely that the blinding was broken in a central location
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "Follow up assessments were available for all 149 patients." Quote: "Thirty‐five patients withdrew prematurely from the study. The reasons were lack of efficacy in 9, adverse events in 15, at the patient’s request in 4, lost to follow‐up in 4, and miscellaneous reasons unrelated to treatment in 3. There was no relationship noted between the dosage of tiludronate and the number of study withdrawals." Comment: Although the reasons for missing outcome data were explained and withdrawals balanced between groups, the proportion of missing outcomes (25%) compared with observed event risk is enough to induce clinically‐relevant bias in intervention 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 no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting insufficient to permit judgement