Fizazi 2009.

Study characteristics
Methods	Recruitment period: 2 December 2004 to 20 January 2008 Outcomes: primary endpoint: proportion of participants with Urinary N‐telopeptide (uNTx) less than 50 at week 13 secondary endpoints: proportion of participants achieving uNTx less than 50 at week 25, time to reduction of uNTx to less than 50, duration of uNTx level less than 50, pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone Pain assessment tool: not given Randomization: denosumab vs bisphosphonates "Patients were randomly assigned in a 1:1:1 ratio to continue intravenous bisphosphonate therapy every 4 weeks or to discontinue IV BP therapy and receive subcutaneous injections of denosumab 180 mg Q4W or Q12W"
Participants	Eligibility criteria: 18 years of age or older, with prostate cancer, other solid carcinomas (except lung cancer), or multiple myeloma with radiographic evidence of 1 or more bone lesions ECOG performance status of 2 or less Exclusion criteria: patients with more than 2 prior SREs, osteonecrosis or osteomyelitis of the jaw patients with planned oral surgery patients with radiotherapy treatment to bone less than 2 weeks before randomization patients with evidence of impending fracture in weight‐bearing bones Participants randomized: 50 participants randomized, 33 in denosumab arm and 17 in bisphosphonate arm Mean age: denosumab 65.9 bisphosphonate 69.5 Country of participants: Europe and North America
Interventions	Previous interventions: most participants with prostate cancer had prior treatment with zoledronic acid and androgen deprivation therapy Interventions during study period: denosumab 180 mg IV bisphosphonates
Outcomes	Reported and analyzed in this review: skeletal complications (pathological bone fracture, spinal cord compression, surgery or radiation therapy to bone, hypercalcemia) adverse events
Funding sources	Funding sources: supported by Amgen Inc.
Declarations of interest	Conflicts of interest: Karim Fizazi: financial interest and/or other relationship with Amgen, Novartis, AstraZeneca, Sanofi‐ Aventis, Ipsen‐Beaufour, Pharmion, Bristol Myers Squibb, and Takeda Linda Bosserman: financial interest and/or other relationship with Amgen and Pfizer Guozhi Gao, Tomas Skacel, and Richard Markus: financial interest and/or other relationship with Amgen
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information on sequence generation
Allocation concealment (selection bias)	Unclear risk	Insufficient information on allocation concealment
Blinding of participants and personnel (performance bias) Blinding of participants	High risk	"phase II, randomized, open label, active controlled study"
Blinding of participants and personnel (performance bias) Blinding of personnel	High risk	"phase II, randomized, open label, active controlled study"
Blinding of outcome assessment (detection bias) Outcomes subjective to participants	High risk	"phase II, randomized, open label, active controlled study"
Blinding of outcome assessment (detection bias) Outcomes subjective to outcome assessors	Unclear risk	"phase II, randomized, open label, active controlled study," but no information on blinding of outcome assessor
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	No information on blinding of outcome assessor, but bias unlikely for objective outcomes
Incomplete outcome data (attrition bias) Time‐to‐event data	Low risk	"The primary analysis was conducted on all patients who were randomized." In both groups there were discontinuations and loss to follow‐up with reasons described.
Incomplete outcome data (attrition bias) Safety data	Low risk	"Safety analyses were performed on randomized patients who received at least 1 dose of investigational drug." In both groups there were discontinuations and loss to follow‐up with reasons described.
Incomplete outcome data (attrition bias) Other outcomes	Unclear risk	In both groups there were discontinuations and loss to follow‐up with reasons described, but not for prostate cancer subgroup alone.
Selective reporting (reporting bias)	Low risk	Study protocol available (NCT00104650); no bias found.
Other bias	Low risk	None identified