Skip to main content
. 2017 Dec 1;2017(12):CD004956. doi: 10.1002/14651858.CD004956.pub3

Fraser 1997.

Methods RCT. Randomisation ratio: 1:1:1:1 (placebo: tiludronate 200 mg, 400 mg, 600 mg).
Superiority design
Participants Diagnostic criteria: Paget's disease confirmed by scintigraphy or radiography or both
Inclusion criteria: Age ≥ 18 years; serum alkaline phosphate concentration at least twice the ULN
Exclusion criteria:

  • prior treatment with bisphosphonates other than etidronate within the past 2 years;

  • treatment with etidronate, mithramycin or calcitonin within 6 months;

  • prior treatment at any time if the current serum alkaline phosphatase concentration was < 30% above the lowest concentration then achieved;

  • recent fracture or confinement to bed;

  • current peptic ulceration;

  • clinically significant liver, kidney or haematological disorder;

  • pre‐menopausal women;

  • malignant neoplasia within the previous 5 years or breast malignancy within the previous 10 years; or

  • recent change in dose of hormone replacement therapy, vitamin D or corticosteroids.


Number screened: not stated.
Number randomised: 112.
Number analysed: 112 (70 years, 54% male, 30% monostotic, 63% symptomatic, percentage previously treated for Paget's disease of bone not stated)
Interventions 4 parallel treatment groups; placebo and tiludronate in 3 doses (200 mg, 400 mg, 600 mg/day) for 12 weeks.
Co‐interventions: Not reported
Outcomes Outcomes reported in abstract
Primary endpoint: Mean percentage change from baseline in serum total alkaline phosphatase activity. Treatment success was defined as 50% reduction in serum alkaline phosphatase concentration compared with baseline after 12 weeks' treatment. (Concentration decreased by 25% or less compared with week 0 reading was defined as resistant).
Secondary endpoints

  • change in bone pain (measured using VAS. Scale ranged from no pain to agonising pain);

  • adverse events related to use of bisphosphonates;

  • radiologically‐confirmed clinical fracture;

  • participants who required orthopaedic surgery;

  • withdrawal due to adverse events; and

  • relapse due to recurrence of bone pain.


Time points for measurement: Baseline, 2 weeks, 8 weeks, 12 weeks, 24 weeks.
How were the outcomes measured: prospectively
Setting and date 16 hospitals in the UK.
Period when the study was conducted: Not stated
Follow up period 6 months. An additional follow‐up to assess the need for re‐treatment was carried out 18 months after the last participant had completed the 6 month trial. Follow‐up was via a postal questionnaire with participants who had completed at least 11 weeks of treatment
Publication details and funding source Language of publication: English.
 Publication status: peer‐reviewed journal; full article.
Funding source: Research supported by Sanofi Winthrop Ltd.
Declarations of interest among primary researchers: Not stated
Notes Tiludronate groups data were pooled for meta‐analysis
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk Quote: "Patients were allocated sequential study numbers and randomly assigned to one of the four treatment groups".
 Comment: Likely there was a central allocation because 16 hospitals recruited participants in the UK
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 study".
Comment: Probably done.
Blinding of outcome assessment (detection bias) 
 All outcomes Unclear risk Insufficient information provided to permit judgement
Incomplete outcome data (attrition bias) 
 All outcomes Low risk Quote: "Data were analysed on an 'intention to treat' basis".
Comment: Reasons for missing outcome data (lost to follow‐up and withdrawals) are reported
Selective reporting (reporting bias) Unclear risk 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.
Quote: "A visual analogue scale was used for patients to assess their Pagetic pain".
Comment: Although stated that "there were no significant differences between any of the treatment groups" data for pain assessment were only provided for placebo and tiludronate higher dose groups
Other bias Unclear risk There were no data on exposure to co‐interventions other than bisphosphonates. No other risks of bias found, but reporting was insufficient to permit judgement