Zoledronate Early to Hip Fracture Patients - Safe and Effective? (ZEBRA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT05025293

Recruitment Status : Recruiting

First Posted : August 27, 2021

Last Update Posted : December 16, 2021

See Contacts and Locations

Sponsor:

Collaborators:

Vestre Viken Hospital Trust

Roche Diagnostics

Information provided by (Responsible Party):

Lene Bergendal Solberg, Oslo University Hospital

Study Description

Brief Summary:

To prevent hip fracture patients for having another fracture, secondary fracture preventing medication should be given as soon as possible. Zoledronate is the most efficient bisphosphonate and is given as an intravenous infusion once yearly. However, the appropriate time to initiate zoledronate treatment after a hip fracture has not yet been established. To clarify the optimal timing of zoledronate to hip fracture patients we have designed a double-blinded, placebo-controlled randomized non-inferiority trial to compare if zoledronate administered early (within 3 days) after hip fracture surgery is as good as zoledronate given late (3 months) after hip fracture surgery.

Condition or disease	Intervention/treatment	Phase
Hip Fractures Osteoporosis	Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj Drug: sodium chloride	Phase 4

Show detailed description

Detailed Description:

Hip fracture patients have the highest risk for recurrent hip or other osteoporotic fractures. We have efficient fracture preventing medication easily available, but few patients receive them. We therefore need to create simple systems to ensure that these frail patients with the highest risk for a new fracture are offered proper treatment early and any delay in treatment should be avoided. Zoledronate is the most efficient bisphosphonate and the drug of choice for hip fracture patients due to the results from the Horizon recurrent fracture trial. It is given as an intravenous infusion once yearly. However, the appropriate time to initiate zoledronate treatment after a hip fracture has not yet been established. The summary of product characteristics (SmPC) for Aclasta (zoledronate) in Norway says that Aclasta should not be administered within the first 2 weeks after the hip fracture, however there have been a practice over years in Norway to give zoledronate to the hip fracture patients during their stay in hospital for fracture treatment. There are logistical and practical advantages of giving zoledronate while the patient is still in hospital for her fracture. It has, however, been questioned whether the effect of zoledronate given within the first 2 weeks postoperatively really is fracture preventing. The results from the post hoc analysis from the Horizon recurrent fracture trial by Eriksen and co-workers in 2009, suggested that given zoledronate within 2-weeks after hip fracture surgery may be a little less fracture preventing. The results from this analysis can be due to the low number of study subjects as well as frailty in the study population causing the large variations. On the other hand, the lack of effect in the within 2-week group may be due to the affinity for zoledronate to bone mineral and the accumulation of zoledronate in the fracture callus during bone repair with less being incorporated in the rest of the skeleton.

To clarify the optimal timing of zoledronate to hip fracture patients we wanted to compare if zoledronate administered early (within 3 days) after hip fracture surgery, while the patients is still in hospital, is as good as zoledronate given late (3 months) after hip fracture surgery.

To test our hypothesis we designed a non-inferiority randomized trial using the bone turnover marker N-terminal propeptide of type I procollagen (P1NP) as the primary endpoint. PINP has in recent years been widely used as a marker to follow the effect of anti-resorptive therapy as it is more robust than the other well studied bone marker; cross-linked C-telopeptide of type I collagen (CTX). P1NP and CTX are recommended as reference markers for bone turnover by the International Osteoporosis Foundation (IOF). Anti-resorptive agents as bisphosphonates influence bone remodeling by decreasing bone resorption (amino-bisphosphonates kills osteoclasts) and thereby also reducing bone formation. This affects the bone turnover markers: Both P1NP and CTX drops in value in a consistent manner reflecting the level of bone suppression and has shown to correlate with the level of bone mineral density and the subsequent fracture risk. P1NP and CTX are therefore well suited to monitor the effect of anti-resorptive therapy as they reflect the bone turnover status in the entire skeleton. It is likely to believe that if zoledronate given early after fracture is accumulated in the fracture callus and too little is incorporated in the entire skeleton, the result will be just a local decrease in bone resorption (only in the fracture callus). This will not to the same extent as a decrease in bone resorption from the entire skeleton, be reflected by the bone turnover markers P1NP and CTX and the fall in these markers will be less than if we give zoledronate after the fracture has healed (after 6-12 weeks).

Eligible patients that meets the study requirements and with an informed consent will be stratified on type of operation (arthroplasty versus internal fixation) and on hospital before randomization 1:1 to either zoledronate early (ZOLearly: zoledronate given within 3 days after hip fracture surgery) or zoledronate late (ZOLlate: zoledronate given 3 months after hip fracture surgery). The patients will be followed for 15 months with study visits at 3 months post fracture and at 6 and 12 months post treatment with zoledronate. The study is double-blinded the first 3 months to be able to test for the "soft" secondary endpoints; delirium and rehabilitation. Approximately 300 patients will be recruited. Estimated recruitment time is 2 years.

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	300 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	Double-blinded randomized controlled non-inferiority trial
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:	The patients are randomized by an electronic system (Viedoc). The randomization is masked for the investigator, the care providers, the participants and the outcomes assessor. Only un-blinded authorized study personnel who prepare the study medicine will see the allocation. The study medicine will be kept in a locked box. Blinded authorized personnel will give the study medication to the patients. The infusions will be covered by a locked box not allowing the patients or others to know the type of infusion.
Primary Purpose:	Prevention
Official Title:	Zoledronate Early to Hip Fracture Patients - Safe and Effective? A Double-blinded Randomized Controlled Treatment Strategy Trial on Zoledronate in Hip Fracture Patients
Actual Study Start Date :	December 15, 2021
Estimated Primary Completion Date :	December 1, 2024
Estimated Study Completion Date :	December 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fractures Hip Injuries and Disorders

Drug Information available for: Zoledronic acid

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: ZOLearly Within 3 days after hip fracture surgery: A single dose of 100 ml containing 5mg zoledronate (Aclasta) will be administered intravenously. The ZOLearly group will have no further infusions during the study period.	Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj 100ml Zoledronic acid (5mg/100ml) administered intravenously Other Names: Zoledronate Aclasta
Placebo Comparator: ZOLlate Within 3 days after hip fracture surgery: A single dose of 100 ml containing 100ml NaCl 9mg/ml (placebo) will be administered intravenously. 3 months after hip fracture surgery (at the out-patient clinic): A single dose of 100 ml containing 5mg zoledronate (Aclasta) will administered intravenously.	Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj 100ml Zoledronic acid (5mg/100ml) administered intravenously Other Names: Zoledronate Aclasta Drug: sodium chloride 100ml NaCl 9mg/ml administered intravenously Other Name: NaCl

Outcome Measures

Primary Outcome Measures :

Difference between the two groups (ZOLearly vs ZOLlate) in proportion of patients having P1NP>35µg/L 12 months after treatment with zoledronate [ Time Frame: 12 months after treatment with zoledronate ]
Measured by the bone turnover marker N-terminal propeptide of type 1 procollagen (P1NP) (µg/ml) in blood samples

Secondary Outcome Measures :

Grade of early mobilization [ Time Frame: 1-30 days ]
Measured by Cumulated Ambulation Score (CAS) in hospital and at discharge from hospital. The score range from 0 to 6, where 6 is the best. The patient is scored daily during the stay in hospital.
Delirium assessment [ Time Frame: 1-30 days ]
Number of patients with delirium assessed by 4 "A" test (4AT) in hospital
Difference between the two groups in proportion of patients having CTX>0.28µg/L 12 months after treatment with zoledronate [ Time Frame: 12 months after treatment with zoledronate ]
Measured by the bone turnover marker C-telopeptide of type 1 collagen (CTX) (µg/ml) in blood samples
Change in bone mineral density (BMD) [ Time Frame: 12 months after treatment with zoledronate ]
Measured by dual-energy x-ray absorbtiometry (DXA) in g/cm2 right after hip fracture surgery and after 12 months with zoledronate treatment
Grade of mobilization and rehabilitation [ Time Frame: 3 months after fracture surgery ]
Measured by Time-up-and-go (TUG) test
Fever (T> 38'C) during hospital stay for fracture surgery [ Time Frame: 1-30 days ]
Temperature measured in 'C in each patient
Use of antibiotics during hospital stay for fracture surgery [ Time Frame: 1-30 days ]
Measure duration of antibiotic treatment in each patient
Hospital stay after hip fracture surgery [ Time Frame: 1-30 days ]
Measure time from admission to discharge from hospital and time from hip fracture surgery to discharge from hospital
Time to readmission to hospital (any department) after first discharge [ Time Frame: 15 months ]
Measure time to first readmission for each patient
Number of readmissions to hospital (any department) after first discharge [ Time Frame: 15 months ]
Measure number of readmissions for each patient
Time to new fracture [ Time Frame: 15 months ]
Measure time to first new fracture after the index fracture for each patient
Total number of new fractures [ Time Frame: 15 months ]
Measure total number of new fractures
Deaths [ Time Frame: 15 months ]
Measure total number of deaths

Other Outcome Measures:

Health-related quality of life [ Time Frame: 12 months after treatment with zoledronate ]
Measured by EQ-5D-5L
Time to fracture healing for the patients with osteosynthesis [ Time Frame: 3 months after fracture treatment ]
Examined by x-rays and TUG test

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information

Ages Eligible for Study:	50 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Low energy hip fracture
Surgery within 72 hours
>50 years old norwegian
Women age 50-60 must be postmenopausal or not pregnant
Acceptable kidney function (estimated GFR >=35) and calcium levels
Fit to complete the follow-up judged by the recruiting physician
Signed informed consent by the patient or the next of kin

Exclusion Criteria:

Metal in the opposite hip
Anti-osteoporosis treatment with bisphosphonates, denosumab, teriparatide, abaloparatide or romosozumab within the last 10 years
Glucocorticoid therapy
Too sick to receive treatment with zoledronate judged by the recruiting or treating physician
Any other contraindication listed on the SmPC of the IMP(s) including pregnancy
Participating in another trial that might affect the current study

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05025293

Contacts

Layout table for location contacts

Contact: Lene B Solberg, PhD MD	+4797669950	l.b.solberg@gmail.com
Contact: Elise B Vesterhus, RN		uxraea@ous-hf.no

Locations

Layout table for location information

Norway
Oslo University Hospital	Recruiting
Oslo, Norway, 0424
Contact: Lene B Solberg, PhD +4797669950 l.b.solberg@gmail.com
Contact: Elise B Vesterhus, RN elise.berg.versterhus@gmail.com

Sponsors and Collaborators

Lene Bergendal Solberg

Vestre Viken Hospital Trust

Roche Diagnostics

Investigators

Layout table for investigator information

Principal Investigator:	Solberg B Lene, PhD MD	Oslo University Hospital

More Information

Layout table for additonal information

Responsible Party:	Lene Bergendal Solberg, Principal Investigator, Oslo University Hospital
ClinicalTrials.gov Identifier:	NCT05025293
Other Study ID Numbers:	2018/2234 2020-000638-17 ( EudraCT Number )
First Posted:	August 27, 2021 Key Record Dates
Last Update Posted:	December 16, 2021
Last Verified:	December 2021

Layout table for additional information

Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No
Product Manufactured in and Exported from the U.S.:	No

Keywords provided by Lene Bergendal Solberg, Oslo University Hospital:


hip fractures zoledronic acid bone turnover markers	delirium early rehabilitation bone mineral density

Additional relevant MeSH terms:

Layout table for MeSH terms

Zoledronic Acid Osteoporosis Fractures, Bone Hip Fractures Wounds and Injuries Bone Diseases, Metabolic Bone Diseases	Musculoskeletal Diseases Metabolic Diseases Femoral Fractures Hip Injuries Leg Injuries Bone Density Conservation Agents Physiological Effects of Drugs

To Top