Trial Outcomes & Findings for Zoledronic Acid in the Prevention of Cancer Treatment Related Bone Loss in Postmenopausal Women Receiving Letrozole for Breast Cancer. (NCT NCT00171340)

NCT ID: NCT00171340

Last Updated: 2012-04-16

Results Overview

Bone Mineral Density (g/cm\^2) of the Lumbar Spine (L2-L4) as measured by energy x-ray absorptiometry (DXA).

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1065 participants
• Primary outcome timeframe: Baseline, 12 months
• Results posted on: 2012-04-16

Participant Flow

Participant milestones

Measure	Zoledronic Acid 4 mg Upfront Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic Acid 4 mg Delayed Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Overall Study STARTED	532	533
Overall Study COMPLETED	408	398
Overall Study NOT COMPLETED	124	135

Reasons for withdrawal

Measure	Zoledronic Acid 4 mg Upfront Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic Acid 4 mg Delayed Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Overall Study Adverse Event	46	42
Overall Study Lack of Efficacy	29	41
Overall Study Protocol Violation	7	8
Overall Study Withdrawal by Subject	22	19
Overall Study Lost to Follow-up	0	5
Overall Study Abnormal Laboratory Results	2	0
Overall Study Abnormal Test Procedure Results	6	11
Overall Study No Longer Required Study Drug	1	1
Overall Study Administrative Problems	5	2
Overall Study Death	6	6

Baseline Characteristics

Zoledronic Acid in the Prevention of Cancer Treatment Related Bone Loss in Postmenopausal Women Receiving Letrozole for Breast Cancer.

Baseline characteristics by cohort

Measure	Zoledronic Acid 4 mg Upfront n=532 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic Acid 4 mg Delayed n=533 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Total n=1065 Participants Total of all reporting groups
Age Continuous	57 Years FULL_RANGE (36-87) • n=5 Participants	58 Years FULL_RANGE (37-81) • n=7 Participants	57 Years n=5 Participants
Sex: Female, Male Female	532 Participants n=5 Participants	533 Participants n=7 Participants	1065 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, 12 months

Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication.

Bone Mineral Density (g/cm^2) of the Lumbar Spine (L2-L4) as measured by energy x-ray absorptiometry (DXA).

Outcome measures

Measure	Zoledronic Acid 4 mg Upfront n=423 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic Acid 4 mg Delayed n=418 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 12 Months of Therapy.	2.208 Percentage change in BMD Standard Deviation 3.4194	-3.617 Percentage change in BMD Standard Deviation 4.2151

SECONDARY outcome

Timeframe: Baseline, 2 years. Baseline, 3 years. Baseline, 4 years. Baseline, 5 years.

Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication. n in each of the categories is the number of participants who had safety data at baseline and the given time point.

Bone Mineral Density (g/cm^2) of the Lumbar Spine (L2-L4) as measured by dual energy x-ray absorptiometry (DXA)

Outcome measures

Measure	Zoledronic Acid 4 mg Upfront n=525 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic Acid 4 mg Delayed n=535 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. At 2 years (n=339,343)	3.463 Percentage change in BMD Standard Deviation 4.2691	-4.601 Percentage change in BMD Standard Deviation 5.5273
Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. At 3 years (n=313,311)	3.730 Percentage change in BMD Standard Deviation 4.884	-4.871 Percentage change in BMD Standard Deviation 6.271
Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. At 4 years (n=290,294)	3.782 Percentage change in BMD Standard Deviation 5.7300	-5.154 Percentage change in BMD Standard Deviation 7.1079
Percentage Change in Bone Mineral Density (BMD) of the Lumbar Spine (L2-L4) at 2, 3, 4 and 5 Years of Therapy. At 5 years (n=264,264)	4.308 Percentage change in BMD Standard Deviation 6.0242	-5.414 Percentage change in BMD Standard Deviation 7.6185

SECONDARY outcome

Timeframe: Baseline, 5 years.

Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication. n in each of the categories is the number of participants who had safety data at baseline and the given time point.

Bone Mineral Density (g/cm^2) of the Lumbar Spine (L1-L4)as measured by dual energy x-ray absorptiometry (DXA)

Outcome measures

Measure	Zoledronic Acid 4 mg Upfront n=525 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic Acid 4 mg Delayed n=535 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. At 12 months (n=360,369)	2.128 Percentage change in BMD Standard Deviation 3.2106	-3603 Percentage change in BMD Standard Deviation 4.1808
Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. At 2 years (n=339,343)	3.300 Percentage change in BMD Standard Deviation 4.0700	-4.521 Percentage change in BMD Standard Deviation 5.2624
Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. At 3 years (n=313,311)	3.521 Percentage change in BMD Standard Deviation 4.5936	-4.869 Percentage change in BMD Standard Deviation 6.0310
Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. At 4 years (n=290,294)	3.529 Percentage change in BMD Standard Deviation 5.5410	-5.148 Percentage change in BMD Standard Deviation 6.8803
Percentage Change in Bone Mineral Density (BMD)of the Lumbar Spine (L1-L4) Over 5 Years of Therapy. At 5 years (n=264,264)	3.898 Percentage change in BMD Standard Deviation 5.7995	-5.427 Percentage change in BMD Standard Deviation 7.4818

SECONDARY outcome

Timeframe: Baseline, 12 months. Baseline, 2 years. Baseline, 3 years. Baseline, 4 years. Baseline, 5 years.

Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication. n in each of the categories is the number of participants who had safety data at baseline and the given time point.

Bone Mineral Density (g/cm^2) of the Lumbar Spine (L2-L4) as measured by dual energy x-ray absorptiometry (DXA)

Outcome measures

Measure	Zoledronic Acid 4 mg Upfront n=525 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic Acid 4 mg Delayed n=535 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. At 12 months (n=419,434)	1.222 Percentage change in BMD Standard Deviation 2.3257	-2.239 Percentage change in BMD Standard Deviation 3.3614
Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. At 2 years (n=394,393)	1.649 Percentage change in BMD Standard Deviation 2.7333	-2.990 Percentage change in BMD Standard Deviation 4.4318
Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. At 3 years (n=376,365)	1.754 Percentage change in BMD Standard Deviation 3.1375	-3.302 Percentage change in BMD Standard Deviation 4.8942
Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. At 4 years (n=336,349)	1.716 Percentage change in BMD Standard Deviation 3.5228	-3.922 Percentage change in BMD Standard Deviation 5.6505
Percentage Change in Bone Mineral Density (BMD) of the Total Hip at 12 Months, 2 Years, 3 Years, 4 Years and 5 Years After Therapy. At 5 years (n=306,314)	1.615 Percentage change in BMD Standard Deviation 3.7490	-4.162 Percentage change in BMD Standard Deviation 6.0270

SECONDARY outcome

Timeframe: Baseline,3 years

Population: The Safety Population consists of all Randomized Patients who received at least 1 dose of study medication.

At 3 years of therapy the percentage of participants with fractures as detected by X-ray and/ or bone scan.

Outcome measures

Measure	Zoledronic Acid 4 mg Upfront n=525 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zoledronic Acid 4 mg Delayed n=535 Participants Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Percentage of Participants With Clinical Fractures at 3 Years of Therapy Which Were Not Present at Baseline	0.6 Percentage of Participants	1.5 Percentage of Participants

Adverse Events

Zoledronic Acid 4mg Upfront

Serious events: 133 serious events

Other events: 477 other events

Deaths: 0 deaths

Zolendronic Acid 4mg Delayed

Serious events: 124 serious events

Other events: 486 other events

Deaths: 0 deaths

Serious adverse events

Measure	Zoledronic Acid 4mg Upfront n=525 participants at risk Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1 and Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zolendronic Acid 4mg Delayed n=535 participants at risk Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Blood and lymphatic system disorders Anaemia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Blood and lymphatic system disorders Febrile neutropenia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Acute myocardial infarction	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Angina pectoris	0.57% 3/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Angina unstable	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Aortic valve incompetence	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Arrhythmia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Atrial fibrillation	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.75% 4/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Atrioventricular block complete	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Cardiac arrest	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Cardiac failure	0.57% 3/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Cardiac failure congestive	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Cardiomegaly	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Coronary artery stenosis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Cytotoxic cardiomyopathy	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Myocardial infarction	0.57% 3/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Myocardial ischaemia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Supraventricular tachycardia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Tachyarrhythmia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Cardiac disorders Tachycardia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Endocrine disorders Goitre	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.56% 3/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Endocrine disorders Hyperparathyroidism	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Endocrine disorders Hyperthyroidism	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Cataract	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Conjunctival haemorrhage	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Diplopia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Eye pain	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Glaucoma	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Iridocyclitis	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Iris cyst	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Macular degeneration	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Retinal disorder	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Vision blurred	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Eye disorders Visual acuity reduced	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Abdominal discomfort	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Abdominal pain	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Abdominal strangulated hernia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Alcoholic pancreatitis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Ascites	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Colitis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Colitis ischaemic	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Colitis ulcerative	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Constipation	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Dental caries	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Diarrhoea	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Diverticulum intestinal	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Femoral hernia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Haematemesis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Haemorrhoids	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Hernial eventration	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Hiatus hernia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Inguinal hernia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Intestinal obstruction	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Intestinal prolapse	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Melaena	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Nausea	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Pancreatitis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Peptic ulcer	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Peritonitis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Reflux oesophagitis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Small intestinal stenosis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Splenic artery aneurysm	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Umbilical hernia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Umbilical hernia, obstructive	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Varices oesophageal	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Vomiting	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Asthenia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Chest discomfort	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Chest pain	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.75% 4/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Death	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders General physical health deterioration	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Impaired healing	0.57% 3/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Inflammation	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Pain	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Pyrexia	0.95% 5/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.56% 3/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Sudden death	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Hepatobiliary disorders Cholecystitis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Hepatobiliary disorders Cholecystitis acute	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Hepatobiliary disorders Cholecystitis chronic	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Hepatobiliary disorders Cholelithiasis	0.76% 4/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	1.9% 10/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Hepatobiliary disorders Hepatic cirrhosis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Hepatobiliary disorders Liver disorder	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Immune system disorders Anaphylactic reaction	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Immune system disorders Hypersensitivity	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Actinomycosis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Biliary tract infection bacterial	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Breast infection	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Bronchopneumonia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Cellulitis	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Device related infection	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Diverticulitis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Erysipelas	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Escherichia sepsis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Gallbladder empyema	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Gastroenteritis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Hepatic infection bacterial	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Herpes zoster	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Incision site cellulitis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Intervertebral discitis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Localised infection	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Lower respiratory tract infection	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Mastitis bacterial	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Pharyngitis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Pneumonia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.75% 4/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Post procedural infection	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Postoperative wound infection	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Pyelonephritis acute	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Respiratory moniliasis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Scrub typhus	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Sepsis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Sinusitis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Staphylococcal sepsis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Urinary tract infection	0.76% 4/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Urosepsis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Wound infection	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Wound infection bacterial	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Accident	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Ankle fracture	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Back injury	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Cartilage injury	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Concussion	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Contusion	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Dislocation of joint prosthesis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Fall	1.3% 7/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	1.3% 7/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Femur fracture	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Fibula fracture	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Hand fracture	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Humerus fracture	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Incisional hernia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Intentional overdose	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Joint dislocation	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Joint sprain	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Meniscus lesion	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Muscle rupture	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Post procedural complication	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Post procedural fistula	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Procedural nausea	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Procedural site reaction	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Radius fracture	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Road traffic accident	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Skin laceration	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Skull fracture	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Tendon rupture	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Traumatic fracture	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Upper limb fracture	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Injury, poisoning and procedural complications Wrist fracture	0.57% 3/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Investigations Bone density decreased	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Investigations Weight decreased	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Metabolism and nutrition disorders Decreased appetite	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Metabolism and nutrition disorders Dehydration	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Metabolism and nutrition disorders Hypercalcaemia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Metabolism and nutrition disorders Hypokalaemia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Metabolism and nutrition disorders Hyponatraemia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Arthralgia	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Arthritis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Arthropathy	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Back pain	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.56% 3/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Bunion	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Dupuytren's contracture	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Foot deformity	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.56% 3/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Ligament disorder	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Monarthritis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Myalgia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.95% 5/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	1.3% 7/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.76% 4/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Pain in extremity	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Pathological fracture	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Tenosynovitis stenosans	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Trigger finger	0.57% 3/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign breast neoplasm	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign gastrointestinal neoplasm	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Benign pancreatic neoplasm	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bowen's disease	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Chronic lymphocytic leukaemia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Fibroadenoma of breast	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma stage 0	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Meningioma benign	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to pleura	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myeloproliferative disorder	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Parathyroid tumour benign	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal cancer	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Salivary gland adenoma	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid cancer	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Brain stem haemorrhage	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Carotid artery stenosis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Carpal tunnel syndrome	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Cerebrovascular accident	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.56% 3/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Depressed level of consciousness	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Facial paresis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Haemorrhagic cerebral infarction	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Headache	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Hemiparesis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Intracranial aneurysm	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Loss of consciousness	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Meningorrhagia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Migraine	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Multiple sclerosis relapse	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Normal pressure hydrocephalus	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Paraesthesia	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Peripheral sensory neuropathy	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Sciatica	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Subarachnoid haemorrhage	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Syncope	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Transient ischaemic attack	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Agitation	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Alcoholic psychosis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Anxiety	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Confusional state	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Depression	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Depression suicidal	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Insomnia	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Mental disorder	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Panic attack	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Suicide attempt	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Renal and urinary disorders Calculus ureteric	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Renal and urinary disorders Hydronephrosis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Renal and urinary disorders Nephrolithiasis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Renal and urinary disorders Nephrotic syndrome	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Renal and urinary disorders Obstructive uropathy	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Renal and urinary disorders Renal colic	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Renal and urinary disorders Renal failure acute	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Renal and urinary disorders Renal impairment	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Renal and urinary disorders Stress urinary incontinence	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Breast atrophy	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Breast calcifications	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Breast fibrosis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.37% 2/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Ovarian cyst	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Perineal fistula	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Rectocele	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Uterine enlargement	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Uterine polyp	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Uterine prolapse	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Vaginal haemorrhage	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Reproductive system and breast disorders Vaginal prolapse	0.38% 2/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Acute pulmonary oedema	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.56% 3/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Increased viscosity of bronchial secretion	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Lung disorder	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Pulmonary congestion	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Pulmonary vascular disorder	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Skin and subcutaneous tissue disorders Pruritus	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Skin and subcutaneous tissue disorders Skin fibrosis	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Skin and subcutaneous tissue disorders Subcutaneous emphysema	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Social circumstances Physical assault	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Vascular disorders Femoral arterial stenosis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Vascular disorders Hypertension	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Vascular disorders Hypertensive crisis	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Vascular disorders Hypotension	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Vascular disorders Lymphoedema	0.19% 1/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.00% 0/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Vascular disorders Varicose vein	0.00% 0/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	0.19% 1/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.

Other adverse events

Measure	Zoledronic Acid 4mg Upfront n=525 participants at risk Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months for 5 years beginning on Day 1 and Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.	Zolendronic Acid 4mg Delayed n=535 participants at risk Zolendronic acid 4 mg Intravenous (IV) 15 minute infusion every 6 months beginning when one of the following occurred: BMD T-score \<= -2.0 SD at either the lumbar spine or total hip, any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the Month 36 visit. All participants took Letrozole tablets 2.5 mg/day for 5 years beginning on Day 1.
Gastrointestinal disorders Abdominal pain upper	3.4% 18/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	5.4% 29/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Constipation	5.1% 27/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	5.8% 31/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Diarrhoea	4.6% 24/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	5.8% 31/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Dyspepsia	4.4% 23/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	5.2% 28/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Gastrointestinal disorders Nausea	9.9% 52/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	10.3% 55/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Asthenia	6.9% 36/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	9.3% 50/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Fatigue	17.7% 93/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	17.8% 95/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Influenza like illness	9.3% 49/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	3.0% 16/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Oedema peripheral	9.3% 49/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	8.8% 47/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
General disorders Pyrexia	14.5% 76/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	3.2% 17/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Nasopharyngitis	6.7% 35/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	5.4% 29/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Infections and infestations Urinary tract infection	3.0% 16/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	6.7% 36/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Investigations Weight decreased	5.9% 31/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	4.3% 23/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Investigations Weight increased	10.9% 57/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	10.7% 57/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Metabolism and nutrition disorders Hypercholesterolaemia	11.0% 58/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	11.2% 60/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Arthralgia	48.8% 256/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	46.9% 251/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Back pain	14.9% 78/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	14.6% 78/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Bone pain	18.5% 97/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	12.0% 64/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	10.9% 57/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	8.4% 45/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Myalgia	13.0% 68/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	13.3% 71/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Neck pain	5.9% 31/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	3.6% 19/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Osteoarthritis	8.0% 42/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	5.2% 28/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Musculoskeletal and connective tissue disorders Pain in extremity	13.1% 69/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	15.0% 80/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Dizziness	5.3% 28/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	7.1% 38/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Nervous system disorders Headache	14.3% 75/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	11.8% 63/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Depression	5.7% 30/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	8.2% 44/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Psychiatric disorders Insomnia	9.7% 51/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	7.1% 38/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Respiratory, thoracic and mediastinal disorders Cough	7.2% 38/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	9.7% 52/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Vascular disorders Hot flush	29.0% 152/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	30.5% 163/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Vascular disorders Hypertension	10.5% 55/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	11.0% 59/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.
Vascular disorders Lymphoedema	7.8% 41/525 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.	6.7% 36/535 Safety Population = Randomized participants who had received at least one dose of randomized treatment medication.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862- 778 8300

Results disclosure agreements

• Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
• Publication restrictions are in place

Restriction type: OTHER